bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteasome β Subunit Pharmacogenomics: Gene Resequencing and Functional Genomics
Authors: Wang Liewei , Kumar Shaji , Fridley Brooke L. , Kalari Krishna R. , Moon Irene , Pelleymounter Linda L. , Hildebrandt Michelle A.T. , Batzler Anthony , Eckloff Bruce W. , Wieben Eric D. , Greipp Philip R.
Published: June 2008

Purpose: The proteasome is a multisubunit cellular organelle that functions as a nonlysosomal threonine protease. Proteasomes play a critical role in the degradation of proteins, regulating a variety of cellular processes, and they are also the target for antineoplastic proteasome inhibitors. Genetic variation in proteasome subunits could influence both proteasome function and response to drug therapy.

Experimental Design: We resequenced genes encoding the three active proteasome β subunits using 240 DNA samples from four ethnic groups and the β5 subunit gene in 79 DNA samples from multiple myeloma patients who had been treated with the proteasome inhibitor bortezomib. Resequencing was followed by functional studies of polymorphisms identified in the coding region and 3′-flanking region (3′-FR) of PSMB5, the gene encoding the target for clinically useful proteasome inhibitors.

Results: Resequencing of 240 DNA samples identified a series of novel ethnic-specific polymorphisms that are not represented in public databases. The PSMB5 3′-FR 1042 G allele significantly increased transcription during reporter gene studies, observations confirmed by genotype-phenotype correlations between single nucleotide polymorphisms (SNP) in PSMB5 and mRNA expression in the 240 lymphoblastoid cell lines from which the resequenced DNA was obtained. Studies with patient DNA samples identified additional novel PSMB5 polymorphisms, including a SNP and an insertion in the 3′-FR. Reporter-gene studies indicated that these two novel polymorphisms might decrease transcription.

Conclusions: These results show that nonsynonymous coding SNPs in the PSMB5 gene did not show significant effects on proteasome activity, but SNPs did influence transcription. Future studies might focus on regulatory region polymorphisms.
Phenotypic Analysis of Prostate-Infiltrating Lymphocytes Reveals TH17 and Treg Skewing
Authors: Sfanos Karen Sandell , Bruno Tullia C. , Maris Charles H. , Xu Lauren , Thoburn Christopher J. , DeMarzo Angelo M. , Meeker Alan K. , Isaacs William B. , Drake Charles G.
Published: June 2008

Purpose: Pathologic examination of prostate glands removed from patients with prostate cancer commonly reveals infiltrating CD4+ and CD8+ T cells. Little is known about the phenotype of these cells, despite accumulating evidence suggesting a potential role for chronic inflammation in the etiology of prostate cancer.

Experimental Design: We developed a technique that samples the majority of the peripheral prostate through serial needle aspirates. CD4+ prostate-infiltrating lymphocytes (PIL) were isolated using magnetic beads and analyzed for subset skewing using both flow cytometry and quantitative reverse transcription-PCR. The transcriptional profile of fluorescence-activated cell sorted prostate-infiltrating regulatory T cells (CD4+, CD25+, GITR+) was compared with naïve, peripheral blood T cells using microarray analysis.

Results: CD4+ PIL showed a paucity of TH2 (interleukin-4–secreting) cells, a surprising finding given the generally accepted association of these cells with chronic, smoldering inflammation. Instead, CD4+ PIL seemed to be skewed towards a regulatory Treg phenotype (FoxP3+) as well as towards the TH17 phenotype (interleukin-17+). We also found that a preponderance of TH17-mediated inflammation was associated with a lower pathologic Gleason score. These protein level data were reflected at the message level, as analyzed by quantitative reverse transcription-PCR. Microarray analysis of pooled prostate-infiltrating Treg revealed expected Treg-associated transcripts (FoxP3, CTLA-4, GITR, LAG-3) as well as a number of unique cell surface markers that may serve as additional Treg markers.

Conclusion: Taken together, these data suggest that TH17 and/or Treg CD4+ T cells (rather than TH2 T cells) may be involved in the development or progression of prostate cancer.
Characterization of TMPRSS2-ERG Fusion High-Grade Prostatic Intraepithelial Neoplasia and Potential Clinical Implications
Authors: Mosquera Juan-Miguel , Perner Sven , Genega Elizabeth M. , Sanda Martin , Hofer Matthias D. , Mertz Kirsten D. , Paris Pamela L. , Simko Jeff , Bismar Tarek A. , Ayala Gustavo , Shah Rajal B. , Loda Massimo , Rubin Mark A.
Published: June 2008

Purpose: More than 1,300,000 prostate needle biopsies are done annually in the United States with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer on subsequent needle biopsies in prostate-specific antigen–screened populations. In contemporary series, prostate cancer is detected in ∼20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histologic subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG gene fusion that has recently been described in prostate cancer has also been shown to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion prostate cancer is associated with a more aggressive clinical course.

Experimental Design: In this study, we assessed a series of HGPIN lesions and paired prostate cancer for the presence of TMPRSS2-ERG gene fusion.

Results: Fusion-positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances, the matching cancer shared the same fusion pattern. Sixty percent of TMPRSS2-ERG fusion prostate cancer had fusion-negative HGPIN.

Conclusions: Given the more aggressive nature of TMPRSS2-ERG prostate cancer, the findings of this study raise the possibility that gene fusion-positive HGPIN lesions are harbingers of more aggressive disease. To date, pathologic, molecular, and clinical variables do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies.
Pathophysiology of Cystic Fibrosis
Authors: Donaldson Scott H. , Boucher Richard C.
Published: June 2008

Understanding the development of lung disease in cystic fibrosis (CF) has been a sought after goal for several decades. With the cloning of the CF transmembrane conductance regulator (CFTR) gene and other advances in the study of airway epithelial biology, a much clearer picture of disease pathophysiology has emerged. Our best available evidence points to dysregulated ion transport as the underlying defect that causes depletion of airway surface liquid volume, i.e. dehydration, and an associated impairment in mucus clearance. Mucostasis in turn predisposes the CF lung to bacterial infection, which rapidly becomes chronic due to the nature of the CF secretions themselves. The nonresolving neutrophilic inflammatory response to this chronic infection in turn causes progressive and permanent airway damage, such that bronchiectasis and respiratory failure are the common findings in end-stage CF lung disease. Hopes of preventing this cascade of events are provided by the development of new therapies that address the underlying defect of airway dehydration.
Diagnostic Procedures, Clinical Characteristics and Counseling in Cystic Fibrosis
Authors: De Boeck Kris
Published: June 2008

Most patients with the eventual diagnosis of cystic fibrosis (CF) present in the first months of life with classical symptoms such as meconium ileus, failure to thrive and recurrent or persistent cough. Disease manifestations are obvious, progressive and concern different organ systems. In these patients the standard diagnostic test is the sweat test. A sweat chloride concentration of >60 mmol/l confirms the clinically suspected diagnosis. Since the discovery of the CFTR (CF transmembrane conductance regulator) gene, it has become obvious that the clinical spectrum is broad. Several categories of patients have been proven to carry two CFTR mutations: patients with classic CF; patients with milder symptoms and disease onset during adolescence or even adulthood; patients with a single clinical feature, e.g. recurrent pancreatitis, sclerosing cholangitis, ‘idiopathic’ bronchiectasis, and male infertility. The latter two categories are described as atypical or non-classic CF. It is very important that these patients know that they do not suffer from classic CF, but that they have a risk factor for developing a CF-like disease that warrants intermittent follow-up by physicians familiar with the very wide disease spectrum. In patients with classic CF, chronic progressive bacterial sinopulmonary infection and inflammation with intermittent exacerbations are the most typical disease manifestations. Ninety percent of patients have pancreatic insufficiency. Postpubertal men are sterile. During their lifetime CF patients may develop disease manifestations and complications in the sinuses, lung, pancreas, liver, intestine, esophagus, bone, joints, etc. The complex mix of possible disease manifestations makes each patient unique. As they become older, the number of complications tends to increase and their physical condition tends to worsen. Many young adult CF patients have decreased exercise tolerance because of advanced lung disease; 20% have CF-related diabetes mellitus. Classic CF is a life-shortening disorder and, even with the most intense treatment and follow-up, the current median survival is around 34 years. This puts an enormous psychological stress on patients and families. Counseling to prevent disease recurrence in siblings and in the extended family is important and complex.
Prosodic Strengthening in Transboundary V-to-V Lingual Movement in American English
Authors: Cho Taehong
Published: June 2008

This study investigates how prosodic strengthening is kinematically manifested in V-to-V lingual movement in English CV#CV context (where # is a prosodic boundary). Results showed that both boundary and accent gave rise to a kind of prosodic strengthening (showing spatial and temporal expansion), but exact kinematic patterns of prosodic strengthening were different as a function of the type of gesture (tongue lowering versus raising) associated with different vowels (/i/to-/É‘/ vs. /É‘/-to-/i/) and the source of prosodic strengthening (boundary versus accentuation). This implies that speakers must know about prosodic structure and differentiate the two sources of prosodic strengthening in a systematic finegrained fashion. From a theoretical point of view regarding a mass-spring gestural model, results suggested that kinematic patterns of prosodic strengthening could not be fully accounted for by any particular dynamical parameter, presenting a complex nature of prosodic strengthening. The results also implied that the theory of the π-gesture (the prosodic boundary gesture) under the rubric of the massspring gestural model needs to be refined in terms of how the theory defines the exact scope of the π-gesture’s influence in the temporal dimension and how it differentiates boundary-induced articulation from an accent-induced one.
Hair Follicles – An Efficient Storage and Penetration Pathway for Topically Applied Substances
Authors: Lademann J. , Knorr F. , Richter H. , Blume-Peytavi U. , Vogt A. , Antoniou C. , Sterry W. , Patzelt A.
Published: June 2008

In the past, it was assumed that the intercellular route was the only relevant penetration pathway for topically applied substances. Recent results on follicular penetration obtained at the Center for Experimental and Applied Cutaneous Physiology, Charité – Universitätsmedizin Berlin, Germany, emphasize that the hair follicles represent a highly relevant and efficient penetration pathway and reservoir for topically applied substances.
Assessment of Quantum Dot Penetration into Intact, Tape-Stripped, Abraded and Flexed Rat Skin
Authors: Zhang L.W. , Monteiro-Riviere N.A.
Published: June 2008

Quantum dot (QD) nanoparticles have received attention due to their fluorescent characteristics and potential use in medical applications. Skin penetration is one of the major routes of exposure for nanoparticles to gain access to a biological system. QD655 and QD565 coated with carboxylic acid were studied for 8 and 24 h in flow-through diffusion cells with flexed, tape-stripped and abraded rat skin to determine if these mechanical actions could perturb the barrier and affect penetration. Nonflexed skin did not show QD penetration at 8 or 24 h. Flexed skin showed an increase in QD on the surface of skin but no penetration at 8 and 24 h. Tape-stripped skin depicted QD only on the surface of the viable epidermis. QD655 penetrated into the viable dermal layers of abraded skin at both 8 and 24 h, while QD565 was present only at 24 h. QD were not detected in the perfusate by fluorescence and inductively coupled plasma-optical emission spectroscopy analysis for cadmium at any time point. These results indicate that the rat skin penetration of QD655 and QD565 is primarily limited to the uppermost stratum corneum layers of intact skin. Barrier perturbation by tape stripping did not cause penetration, but abrasion allowed QD to penetrate deeper into the dermal layers.
Optical Methods for Measurements of Skin Penetration
Authors: Gotter B. , Faubel W. , Neubert R.H.H.
Published: June 2008

Fourier transform infrared photoacoustic (PAS), photothermal deflection (PDS) and Raman spectroscopy belong to the modern innovative noninvasive analytical tools that are beginning to be recognized as highly potential techniques for the noninvasive study of biological tissues and human skin under in vivo conditions. They can be applied to obtain information regarding the molecular composition of the skin down to several hundred micrometers below the skin surface. All three methods allow depth-resolved investigations. While PAS and PDS use a frequency modulation of the excitation beam to reach deeper regions in the sample, the principle of confocal Raman microspectroscopy (CRM) is a movement of the specimen in the focal plane. In consideration of depth measurements PAS and PDS complete the applicable spectrum of CRM, since Raman microscopy requires particular transparent materials.
Genes and Neuroimaging: Advances in Psychiatric Research
Authors: Gallinat J. , Bauer M. , Heinz A.
Published: June 2008

Major psychiatric disorders, including schizophrenia, bipolar disorder and substance addiction, are partly heritable and show a multifactorial pattern of heredity. Although the introduction of explicit diagnostic criteria has improved clinical research on psychiatric disorders, the concept is only of limited use for exploring their genetic underpinnings. On the behavioral level, psychopathological symptoms can hardly separate the many pathophysiological subgroups. Contrary to nosological categories, biologically based phenotypes – referred to as intermediate phenotypes – consisting of neuropsychological, electrophysiological, functional and structural brain imaging parameters, could represent the genetic basis more directly. Thus intermediate phenotypes are being targeted in current molecular genetic investigations. In this article, we review existing data on the effects of genetic variation in the dopamine and serotonin systems (catechol-O-methyltransferase, the serotonin-transporter-linked polymorphic region) on the morphometric, metabolic and functional characteristics of the cerebral cortex and limbic structures. The gene-driven modulation of these brain circuits is discussed with regard to their behavioral correlates and their role for psychiatric diseases. Furthermore, recently identified putative susceptibility genes for schizophrenia (neuregulin 1, dysbindin, G72) are briefly discussed.
Towards Noninvasive Molecular Fluorescence Imaging of the Human Brain
Authors: Steinbrink J. , Liebert A. , Wabnitz H. , Macdonald R. , Obrig H. , Wunder A. , Bourayou R. , Betz T. , Klohs J. , Lindauer U. , Dirnagl U. , Villringer A.
Published: June 2008

Fluorescence molecular brain imaging is a new modality allowing the detection of specific contrast agents down to very low concentration ranges (picomolar) in disease models. Here we demonstrate a first noninvasive application of fluorescence imaging in the human brain, where concentrations down to about 100 nM of a nonspecific dye were detected. We argue that due to its high sensitivity, optical molecular imaging of the brain is feasible, which – together with its bedside applicability – makes it a promising technique for use in patients.
Coexisting Cholinergic and Parahippocampal Degeneration: A Key to Memory Loss in Dementia and a Challenge for Transgenic Models?
Authors: Cassel Jean-Christophe , Mathis Chantal , Majchrzak Monique , Moreau Pierre-Henri , Dalrymple-Alford John C.
Published: June 2008

One century after Alzheimer’s initial report, a variety of animal models of Alzheimer’s disease (AD) are being used to mimic one or more pathological signs viewed as critical for the evolution of cognitive decline in dementia. Among the most common are, (a) traditional lesion models aimed at reproducing the degeneration of one of two key brain regions affected in AD, namely the cholinergic basal forebrain (CBF) and the transentorhinal region, and (b) transgenic mouse models aimed at reproducing AD histopathological hallmarks, namely amyloid plaques and neurofibrillary tangles. These models have provided valuable insights into the development and consequences of the pathology, but they have not consistently reproduced the severity of memory deficits exhibited in AD. The reasons for this lack of correspondence with the severity of expected deficits may include the limited replication of multiple neuropathology in potentially key brain regions. A recent lesion model in the rat found that severe memory impairment was obtained only when the two traditional lesions were combined together (i.e. conjoint CBF and entorhinal cortex lesions), indicative of a dramatic impact on cognitive function when there is coexisting, rather than isolated, damage in these two brain regions. It is proposed that combining AD transgenic mouse models with additional experimental damage to both the CBF and entorhinal regions might provide a unique opportunity to further understand the evolution of the disease and improve treatments of severe cognitive dysfunction in neurodegenerative dementias.
The Endoplasmic Reticulum Stress-Mediated Apoptosis Signal Pathway Is Involved in Sepsis-Induced Abnormal Lymphocyte Apoptosis
Authors: Ma T. , Han L. , Gao Y. , Li L. , Shang X. , Hu W. , Xue C.
Published: June 2008

Background/Aim: The mechanisms of abnormal lymphocyte apoptosis in sepsis are only partially defined. The present study was designed to investigate whether the endoplasmic reticulum (ER) is implicated in the extensive apoptosis of lymphocytes in sepsis. Methods: C57BL/6 mice were randomized into cecal ligation and puncture (CLP) and sham operation groups. Apoptosis was detected by the TUNEL method and flow cytometry. The expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) was detected by RT-PCR and Western blot. The splicing of X box-binding protein-1 (XBP1) mRNA was detected by RT-PCR. Results: A high degree of lymphocyte apoptosis was observed in the CLP group. Marked induction of GRP78 and accumulation of spliced XBP1 mRNA were observed in the splenocytes from septic mice, indicating activation of unfolded protein responses. Furthermore, both CHOP and its mRNA were markedly upregulated in the CLP group, suggesting that the ER stress response switched to a proapoptotic response. Conclusion: These data demonstrate activation of the unfolded protein response in lymphocytes and that ER stress may contribute to abnormal lymphocyte apoptosis during sepsis. Accordingly, the ER stress-mediated apoptosis pathway may be a novel target in clinical prevention and therapy of sepsis-induced lymphocyte apoptosis.
Characterization of Rabbit Ear Skin as a Skin Model for in vitro Transdermal Permeation Experiments: Histology, Lipid Composition and Permeability
Authors: Nicoli S. , Padula C. , Aversa V. , Vietti B. , Wertz P.W. , Millet A. , Falson F. , Govoni P. , Santi P.
Published: June 2008

Aim: The aim of this work was to characterize rabbit ear skin in view of its use in transdermal permeation experiments. Method: The characterization included histological analysis of the tissue, qualitative and quantitative analysis of stratum corneum (SC) lipids, differential scanning calorimetry and permeation experiments (caffeine, nicotinamide, progesterone). As a reference, pig ear skin was used. Results: The results obtained show that rabbit ear skin has a similar SC thickness compared to pig skin although the viable epidermis has a different structure. The lipid composition of rabbit SC was similar to pig SC but was characterized by a lower content of ceramides and a higher content of cholesterol esters and triglycerides. In terms of permeability, rabbit ear skin was 4–7 times less permeable to hydrophilic compounds, probably because of the higher lipophilicity of its SC. The permeability to progesterone was comparable between isolated pig epidermis and rabbit ear skin. Conclusion: Overall, the results obtained in this work support the usefulness of rabbit ear skin as barrier for skin penetration studies, for both lipophilic and hydrophilic permeants.
Typical and Atypical Antipsychotics – The Misleading Dichotomy
Authors: Fischer-Barnicol David , Lanquillon Stefan , Haen Ekkehard , Zöfel Peter , Koch Horst J. , Dose Matthias , Klein Helmfried E.
Published: June 2008

Objectives: (1) To investigate the risk of extrapyramidal motor side effects (EPS) associated with the prescription of different antipsychotics under naturalistic treatment conditions; (2) to test the rationale of the terms ‘typical’ and ‘atypical’ based on EPS rates. Design: Cross-sectional study in the federal state of Bavaria. Setting: 20 psychiatric hospitals in Bavaria. Participants: 6,061 inpatients, aged 18–65 years, with psychotic disorders. Main Outcome Measures: Co-medication with the anticholinergic biperiden was used as an index of EPS. Odds ratios for EPS and numbers needed to harm [number of patients who would need to be treated to obtain one more case with an adverse outcome (i.e. EPS) as compared with the control treatment (clozapine)] were calculated to obtain risk estimates for 15 different antipsychotics. Results: Groups of ‘typical’ and ‘atypical’ antipsychotics were not homogeneous in their EPS rates, and showed wide variation within each group. Nor did the frequency of EPS allow a clear distinction between the groups. There were 2 reasons for this: first, EPS rates rose continuously over the whole spectrum of drugs under study, and therefore precluded the definition of a cut-off score; second, there was considerable overlap between the 2 groups as EPS rates of various ‘atypicals’ (e.g. amisulpride, risperidone and zotepine) did not differ from some ‘typical’ substances (e.g. fluphenazine), while one ‘typical’ antipsychotic (perazine) even had a lower EPS risk than most ‘atypicals’. Conclusions: The odds of inducing EPS are not distinguishable between ‘typical’ and ‘atypical’ antipsychotics as EPS rates rise on a continuous scale throughout both classes. We propose dropping the categorization of antipsychotics as ‘typical’ and ‘atypical’ and instead using risk estimates like number needed to harm for EPS to help in benefit/risk considerations for antipsychotic treatment.
Meta-Analysis of Genetic Studies from Journals Published in China of Ischemic Stroke in the Han Chinese Population
Authors: Xu Xiaowei , Li Jiejie , Sheng Wenli , Liu Lin
Published: June 2008

Background: The aim of this study was to confirm the nature and number of genes contributing to stroke risk and qualify the genetic risk of each susceptibility gene in the Han Chinese population. Methods: After collecting all case-control studies related to DNA polymorphism of any candidate gene for ischemic stroke in Han Chinese, strict selection criteria and exclusion criteria were determined and different effect models were used according to the difference in heterogeneity. Meta-analyses were carried out by Revman 4.0 software and the publication bias was further evaluated through calculation of fail-safe numbers in the included gene polymorphisms. Results: Seventy-six studies were included in the meta-analyses which were all published in mainland China and referred to 6 candidate genes and 7 polymorphisms. Among the gene polymorphisms tested in the study, association of gene polymorphisms with increasing risk of ischemic stroke was confirmed in 6 polymorphisms including angiotensin-converting enzyme insertion/deletion (ACE I/D; OR = 1.87, 95% CI = 1.45–2.42), methylenetetrahydrofolate reductase (MTHFR) C677T (OR = 1.55, 95% CI = 1.26–1.90), plasminogen activator inhibitor 1 (PAI-1) 4G/5G (OR = 1.79, 95% CI = 1.20–2.67), β-fibrinogen (β-Fg) –455A/G (OR = 1.48, 95% CI = 1.14–1.92), β-Fg –148T/C (OR = 1.72, 95% CI = 1.42–2.07), apolipoprotein E (ApoE) Ε2–4 (OR = 2.39, 95% CI = 1.94–2.95). Because of the obvious publication bias, the association between paraoxonase 1 (PON-1) polymorphisms and stroke risk was not established although the OR of the meta-analysis suggested a positive result (OR = 1.14, 95% CI = 1.01–1.35). Conclusions: ACE D/I, MTHFR C677T, β-Fg –455A/G, β-Fg –148T/C, PAI-1 4G/5G, and ApoE Ε2–4 were associated with risk of ischemic stroke in Han Chinese.
Increased Values of Mean Platelet Volume and Platelet Size Deviation Width May Provide a Safe Positive Diagnosis of Idiopathic Thrombocytopenic Purpura
Authors: Ntaios George , Papadopoulos Athanasios , Chatzinikolaou Anastasia , Saouli Zoi , Karalazou Paraskevi , Kaiafa Georgia , Girtovitis Fotios , Kontoninas Zisis , Savopoulos Christos , Hatzitolios Apostolos , Alexiou-Daniel Stiliani
Published: June 2008

Introduction: It has been shown recently that platelet indices like mean platelet volume (MPV), platelet size deviation width (PDW) and platelet-to-large-cell ratio (P-LCR) are helpful in the discrimination between hyperdestructive thrombocytopenia like idiopathic thrombocytopenic purpura (ITP) and hypoproductive thrombocytopenia (HT). The aim of the study is to assess the reliability of these indices in the differentiation of ITP from other thrombocytopenias. Methods: We recruited 134 thrombocytopenic patients (69 men, 65 women) who were divided into two groups according to the underlying disease: group I (n = 63) included ITP patients, whereas group II (n = 71) included patients with HT due to myelosuppression secondary to chemotherapy for hematological malignancies. Platelet indices were derived from a Sysmex automated cell counter. Sensitivity, specificity, positive prognostic value, negative prognostic value, efficiency and Youden index were calculated. Results: Concerning MPV and PDW indices, sensitivity, specificity, positive prognostic value, negative prognostic value, efficiency and Youden index were 100% for the diagnosis of ITP. On the contrary, the values for P-LCR were significantly lower. Conclusions: MPV and PDW can be safely relied on for a positive diagnosis of ITP. MPV and PDW were superior to P-LCR.
Increased cAMP Signaling Can Ameliorate the Hypertensive Condition in Spontaneously Hypertensive Rats
Authors: Berg Torill , Degerman Eva , Tasken Kjetil
Published: June 2008

Background/Aim: Augmented adrenergic control of total peripheral vascular resistance (TPVR) in spontaneously hypertensive rats (SHR) may result from deficiencies in the vasodilatory system(s). Here, we studied the effect of cyclic AMP (cAMP) on TPVR-baseline and adrenergic vasoconstriction in SHR and normotensive controls (WKY). Methods: Blood pressure and cardiac output were monitored in anesthetized rats, and TPVR calculated. Results: cAMP-analogue (8CPT-cAMP) and phosphodiesterase (PDE) 3 inhibitor (milrinone) reduced TPVR in both strains. Gi inactivator (pertussis toxin) lowered TPVR but not in all SHR. ΔTPVR induced by α1-adrenoceptor agonist (phenylephrine) was reduced by 8CPT-cAMP and milrinone in both strains. They also clearly reduced the response to endogenous noradrenaline release (tyramine) in SHR but had little effect in WKY. When pertussis toxin reduced baseline, it also eliminated the tyramine TPVR response. Propranolol did not change the effect of milrinone on the phenylephrine or tyramine response. Strain-related differences in aorta, femoral arteries or skeletal muscle PDE activity (total/PDE3/PDE4) were absent. Conclusions: cAMP signaling down-stream of cAMP was functional in SHR, and opposed α1-adrenoceptor vasoconstriction in both strains. Gi activity greatly influenced the TPVR baseline and adrenergic TPVR responses, and its activity appeared increased in SHR. Therapeutics aiming to increase signaling through this pathway may turn out to be valuable in the treatment of hypertension.
7-Ketocholesterol Upregulates Interleukin-6 via Mechanisms That Are Distinct from Those of Tumor Necrosis Factor-α, in Vascular Smooth Muscle Cells
Authors: Sung Si-Chan , Kim Koanhoi , Lee Kyeong-Ah , Choi Kyung-Ha , Kim Sun-Mi , Son Yong-Hae , Moon Yu-Seok , Eo Seong-Kug , Rhim Byung-Yong
Published: June 2008

This study investigated the effects of 7-ketocholesterol on interleukin (IL)-6 expression in vascular smooth muscle cells (VSMC). Among the 7 IL examined, only IL-6 transcript was increased by 7-ketocholesterol treatment in human aorta smooth muscle cells. IL-6 transcripts increased up to 24 h after treatment with 7-ketocholesterol, and this effect was profoundly repressed by treatment with p38 MAPK inhibitors and to a lesser extent JNK inhibitors. 7α-Hydroxycholesterol, 27-hydroxycholesterol or cholesterol, however, did not induce IL-6 expression. Mechanisms of IL-6 induction by 7-ketocholesterol were investigated in comparison with tumor necrosis factor (TNF)-α. Whereas TNF-α activated IL-6 promoter, which was impaired by p38 MAPK inhibitors or by mutation in the NF-κB-binding site within the promoter region, 7-ketocholesterol did not affect IL-6 promoter activity. Instead, this oxysterol slowed degradation of IL-6 mRNA and increased the amount of cytoplasmic HuR. 7-ketocholesterol significantly increased the amount of intracellular IL-6 protein in the presence of brefeldin A. 7-Ketocholesterol also enhanced IL-6 release from VSMC. IL-6 release by 7-ketocholesterol, although significant, was not as remarkable as that induced by TNF-α. These data suggest that 7-ketocholesterol upregulates IL-6 via mechanisms distinct from TNF-α and contributes to the intra- and extracellular IL-6 deposits within the vasculature.
Short-Term Effects of N-Acetylcysteine and Ischemic Preconditioning in a Canine Model of Hepatic Ischemia-Reperfusion Injury
Authors: Baumann J. , Ghosh S. , Szakmany T. , Jancso G. , Ferencz A. , Roth E. , Bogar L.
Published: June 2008

Aims: We evaluated the possibility that repeated ischemic preconditioning or N-acetylcysteine (NAC) could prevent ischemia-reperfusion injury as determined by indocyanine green plasma disappearance rate (ICG-PDR) or has favorable hemodynamic effects during reperfusion in an in vivo canine liver model. Methods: Under general anesthesia, 3 groups of mongrel dogs (n = 5 per group) were subjected to (1) 60-min hepatic ischemia, (2) same ischemia preceded by intravenous administration of 150 mg kg–1 NAC, and (3) three episodes of IPC (10-min ischemia followed by 10-min reperfusion) prior to same ischemia. Hepatic reperfusion was maintained for a further 180 min, with hemodynamic and hepatic function parameters monitored throughout. Results: Plasma disappearance rate of indocyanine green and serum levels of aspartate transferase and alanine transferase showed no significant differences between groups. Although liver injury was obvious, reflected by hemodynamic, blood gas, and liver function tests, NAC and IPC failed to prevent decay in hepatic function in this canine model. Conclusion: The results do not support the hypothesis that short-term use of NAC and IPC is beneficial in hepatic surgery.
Expression of the WASP Verprolin-Homologues (WAVE Members) in Human Breast Cancer
Authors: Fernando H.S. , Davies S.R. , Chhabra A. , Watkins G. , Douglas-Jones A. , Kynaston H. , Mansel R.E. , Jiang W.G.
Published: June 2008

Background: The WASP family proteins have been indicated to play a vital role in the formation of membrane protrusions required for cell locomotion. WAVE proteins are an important subfamily that also plays a crucial role in actin polymerisation, which is vital to cell migration. However, not much is known about the clinical significance of this subfamily in cancers. We report, for the first time, the expression of the WAVE molecules, at protein and mRNA levels, in human breast cancer. Materials and Methods: The expression of the 3 WAVE molecules at the mRNA and protein levels in a cohort of 122 human breast cancers and 32 normal breast tissues were analysed and correlated with the patients’ pathological and clinical information as well as outcome (120 months follow-up). Results: All 3 WAVE molecules were detected in mammary tissues. WAVE2 transcripts were expressed in high levels in all breast tumours. Over-expression of WAVE2 was seen in node-positive cases as well as in moderately and poorly differentiated tumours. Also, high levels of WAVE2 expression were associated with death due to disease (p = 0.02) at follow-up. No distinct associations were found between the WAVE1 and WAVE3 transcripts and the breast cancer cells.
Outcome of Patients with Melanoma and Histologically Negative Sentinel Lymph Nodes: One Institution’s Experience
Authors: De Giorgi Vincenzo , Leporatti Genny , Massi Daniela , Lo Russo Giulia , Sestini Serena , Dini Mario , Lotti Torello
Published: June 2008

Background: Since its introduction by Morton in 1992, sentinel lymph node (SLN) biopsy has become a standard procedure in the staging and treatment of primary melanoma and clinically negative regional lymph nodes. The primary aims of this procedure are to ascertain the individual lymphatic drainage patterns of primary tumors towards 1 or more different lymph node basins and to identify patients with micrometastatic lymphatic disease for selective lymphadenectomy. The aim of our study was to evaluate over time a cohort of patients who, having undergone SLN treatment, were found negative for metastases using routine histopathological and immunohistochemical analyses. Methods: We studied 102 consecutive patients who underwent intraoperative lymphatic mapping at the Department of Plastic Surgery, University of Florence, Italy, for cutaneous melanoma and were found negative for metastatic melanoma in their SLNs using routine histopathological and immunohistochemical techniques. Results: Of 102 patients with 103 cutaneous melanomas that underwent SLN resection and proved histologically negative to metastasis in that site, 15 patients (14.7%) developed melanoma recurrence during follow-up. Conclusions: The diagnostic and prognostic value of the absence of melanoma metastases in SLNs may be limited and not particularly significant, since satellite and in-transit metastases or direct distant metastases will not be detected and hematogenous spread may already have begun at the time of intervention.
Late Relapse of Stage I Seminoma following Single-Agent Carboplatin
Authors: Raj S. , Williams M.V. , Dixon A.K. , Robson J. , Mazhar D.
Published: June 2008

We present a case report of a patient who received adjuvant carboplatin for stage 1 seminoma and relapsed with abdominal lymph node metastasis at 48 months. In recent years, many oncologists have offered a single cycle of adjuvant carboplatin AUC7 as adjuvant treatment for stage 1 seminoma. The available data show a non-inferior relapse-free survival at 3 years compared with para-aortic radiotherapy. The rate of relapse beyond this point has not been reported. Patients with stage 1 seminoma represent a group of patients with excellent outcomes, and treatment options must also consider the late effects of treatment, of which there are increasing data of mortality for those treated with radiotherapy. Patients who opt for surveillance have a greater than 80% chance of remaining relapse free at 5 years, but those on surveillance require more CT examinations for follow-up. For those treated with single-agent carboplatin, our case report highlights that late relapse can occur, and we suggest that CT surveillance beyond 2 years is required given the lack of mature data on late relapse.
A Cautionary Note on the Use of Nonparametric Bootstrap for Estimating Uncertainties in Extreme-Value Models
Authors: Kyselý Jan
Published: June 2008

The parametric and nonparametric approaches to the bootstrap are compared as to their performance in estimating uncertainties in extreme-value models. Simulation experiments make use of several combinations of true and fitted probability distributions utilized in climatological and hydrological applications. The results demonstrate that for small to moderate sample sizes the nonparametric bootstrap should be interpreted with caution because it leads to confidence intervals that are too narrow and underestimate the real uncertainties involved in the frequency models. Although the parametric bootstrap yields confidence intervals that are slightly too liberal as well, it improves the uncertainty estimates in most examined cases, even under conditions in which an incorrect parametric model is adopted for the data. Differences among three examined types of bootstrap confidence intervals (percentile, bootstrap t, and bias corrected and accelerated) are usually smaller in comparison with those between the parametric and nonparametric versions of bootstrap. It is concluded that the parametric bootstrap should be preferred whenever inferences are based on small to moderate sample sizes (n ≤ 60) and a suitable model for the data is known or can be assumed, including applications to confidence intervals related to extremes in global and regional climate model projections.
Fast Lidar and Radar Multiple-Scattering Models. Part I: Small-Angle Scattering Using the Photon Variance–Covariance Method
Authors: Hogan Robin J.
Published: June 2008

A fast, approximate method is described for the calculation of the intensity of multiply scattered lidar returns from clouds. At each range gate it characterizes the outgoing photon distribution by its spatial variance, the variance of photon direction, and the covariance of photon direction and position. The result is that for an N-point profile the calculation is O(N) efficient yet it implicitly includes all orders of scattering, in contrast with the O(Nm/m!) efficiency of models that explicitly consider each scattering order separately for truncation at m-order scattering. It is also shown how the shape of the scattering phase function near 180° may be taken into account for both liquid water droplets and ice particles. The model considers only multiple scattering due to small-angle forward-scattering events, which is suitable for most ground-based and airborne lidars because of their small footprint on the cloud. For spaceborne lidar, it must be used in combination with the wide-angle multiple scattering model described in Part II of this two-part paper.
Controls of Global-Mean Precipitation Increases in Global Warming GCM Experiments
Authors: Stephens Graeme L. , Ellis Todd D.
Published: June 2008

This paper examines the controls on global precipitation that are evident in the transient experiments conducted using coupled climate models collected for the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4). The change in precipitation, water vapor, clouds, and radiative heating of the atmosphere evident in the 1% increase in carbon dioxide until doubled (1pctto2x) scenario is examined. As noted in other studies, the ensemble-mean changes in water vapor as carbon dioxide is doubled occur at a rate similar to that predicted by the Clausius–Clapeyron relationship. The ratio of global changes in precipitation to global changes in water vapor offers some insight on how readily increased water vapor is converted into precipitation in modeled climate change. This ratio ɛ is introduced in this paper as a gross indicator of the global precipitation efficiency under global warming.

The main findings of this paper are threefold. First, increases in the global precipitation track increase atmospheric radiative energy loss and the ratio of precipitation sensitivity to water vapor sensitivity is primarily determined by changes to this atmospheric column energy loss. A reference limit to this ratio is introduced as the rate at which the emission of radiation from the clear-sky atmosphere increases as water vapor increases. It is shown that the derived efficiency based on the simple ratio of precipitation to water vapor sensitivities of models in fact closely matches the sensitivity derived from simple energy balance arguments involving changes to water vapor emission alone. Second, although the rate of increase of clear-sky emission is the dominant factor in the change to the energy balance of the atmosphere, there are two important and offsetting processes that contribute to ɛ in the model simulations studied: One involves a negative feedback through cloud radiative heating that acts to reduce the efficiency; the other is the global reduction in sensible heating that counteracts the effects of the cloud feedback and increases the efficiency. These counteracting feedbacks only apply on the global scale. Third, the negative cloud radiative heating feedback occurs through reductions of cloud amount in the middle troposphere, defined as the layer between 680 and 440 hPa, and by slight global cloud decreases in the lower troposphere. These changes act in a manner to expose the warmer atmosphere below to high clouds, thus resulting in a net warming of the atmospheric column by clouds and a negative feedback on the precipitation.
Observed and CAM3 GCM Sea Surface Wind Speed Distributions: Characterization, Comparison, and Bias Reduction
Authors: Capps Scott B. , Zender Charles S.
Published: June 2008

Climatological surface wind speed probability density functions (PDFs) estimated from observations are characterized and used to evaluate, for the first time, contemporaneous wind PDFs predicted by a GCM. The observations include NASA’s global Quick Scatterometer (QuikSCAT) dataset, the NCEP/Department of Energy Global Reanalysis 2 (NCEP-2) 6-hourly reanalysis, and the Tropical Atmosphere Ocean (TAO)/Triangle Trans-Ocean Buoy Network (TRITON) moored buoy data, all from 2000 to 2005. Wind speed mean, 90th percentile, standard deviation, and Weibull shape parameter climatologies are constructed from these data. New features that emerge from the analysis include the identification of a stationary pattern to the wind speed variance in the equatorial Pacific. Interestingly, a distinct wind speed shape anomaly migrates with the ITCZ across this stationary background.

The GCM despite its coarser spatial and temporal resolution predicts wind speed PDFs in general agreement with observations. Relative to QuikSCAT, the NCAR Community Atmosphere Model, version 3 (CAM3) GCM has a globally averaged positive mean wind speed bias of about 0.2 m s−1 originating primarily within the trades and Southern Hemisphere storm track. Global standard deviation biases are largest in the winter hemisphere storm tracks. The largest shape biases occur along the equatorial peripheries of the Northern Hemisphere and southern Indian Ocean anticyclones. Year-round negative shape and mean wind speed biases persist along the ITCZ. The GCM’s overactive tropical convection and slight subtropical anticyclone displacement contribute to positive mean speed, standard deviation, and shape trade biases.

Surface heat and energy fluxes depend nonlinearly on wind speed magnitude, are sensitive to the tails of the wind distribution, and hence vary significantly on spatiotemporal scales not resolved by GCMs. Limited computing resources force the use of coarse-resolution GCMs, which do not resolve finer-scale wind speed fluctuations. Rather, surface fluxes are determined from the mean wind speed computed by averaging spatially and temporally over subgrid-scale features. Some surface flux routines account for gustiness during low mean winds resulting from thermally driven convection. The authors hypothesize that GCMs systematically underestimate surface momentum flux nonlinearities and that this biases surface wind predictions most in regions of strong winds with high variability. To test this, climate simulations that account for surface fluxes due to subgrid-scale GCM winds are performed. This significantly improves climatological surface wind speed statistics, particularly in the Southern Hemisphere storm track, consistent with the hypothesis. These wind speed improvements can be attributed to a reduction in GCM sea level pressure biases throughout the globe.
Sensitivity of Numerical Simulation of Early Rapid Intensification of Hurricane Emily (2005) to Cloud Microphysical and Planetary Boundary Layer Parameterizations
Authors: Li Xuanli , Pu Zhaoxia
Published: June 2008

An advanced research version of the Weather Research and Forecasting (ARW) Model is used to simulate the early rapid intensification of Hurricane Emily (2005) using grids nested to high resolution (3 km). A series of numerical simulations is conducted to examine the sensitivity of the simulation to available cloud microphysical (CM) and planetary boundary layer (PBL) parameterization schemes. Results indicate that the numerical simulations of the early rapid intensification of Hurricane Emily are very sensitive to the choice of CM and PBL schemes in the ARW model. Specifically, with different CM schemes, the simulated minimum central sea level pressure (MSLP) varies by up to 29 hPa, and the use of various PBL schemes has resulted in differences in the simulated MSLP of up to 19 hPa during the 30-h forecast period. Physical processes associated with the above sensitivities are investigated. It is found that the magnitude of the environmental vertical wind shear is not well correlated with simulated hurricane intensities. In contrast, the eyewall convective heating distributions and the latent heat flux and high equivalent potential temperature (θe) feeding from the ocean surface are directly associated with the simulated intensities. Consistent with recognized facts, higher latent heat release in stronger eyewall convection, stronger surface energy, and high θe air feeding from the ocean surface into the hurricane eyewall are evident in the more enhanced convection and intense storms. The sensitivity studies in this paper also indicate that the contributions from the CM and PBL processes can only partially explain the slow intensification in the ARW simulations. Simulation at 1-km grid resolution shows a slight improvement in Emily’s intensity forecast, implying that the higher resolution is somewhat helpful, but still not enough to cause the model to reproduce the real intensity of the hurricane.
Researching Participation in Adult Education: The Potential of the Qualitative Perspective
Authors: Rockhill Kathleen
Published: June 2008

Current research on participation is critiqued in terms of problems in exact measurement, superimposed definitions, and the use of value-laden constructs. Building upon the thesis that the qualitative and quantitative approaches to research represent different perspectives, they are compared in terms of purpose, their interpretations, premises, focus, method, and research criteria, including reliability and validity. The qualitative perspective, particularly as influenced by hermeneutics and social phenomenology, is developed further and implications for the study of participation are considered. Emphasis is placed upon the importance of understanding the meaning of participation in the life-world of the individual. Educational participation is considered within the broader context of learning, and learning is viewed as embedded in the life-world.