bluuebunny/crossref_metadata_2025 huggingface dataset:
Endovascular Thoracic Aortic Aneurysm Repair without Angiography
Authors: Tozzi Piergiorgio , Marty Bettina , Ruchat Patrick , Ferrari Enrico , Siniscalchi Giuseppe , von Segesser Ludwig K.
Published: February 2009

Objective

Intravascular ultrasound (IVUS) generates high definition circumferential cross-sectional images and provides real-time readout of vascular dimensions, including visualization of vessel branches. We have used it as an alternative to angiography in the endovascular thoracic aneurysm repair work-up.

Methods

Out of consecutive 203 patients with descending thoracic aortic aneurysm, 89 (43.8%) received endovascular treatment [mean age, 68 ± 8 years; range, 29–82; male, 79 (88.7%); female, 10 (11.3%)] without using angiography during the endovascular procedure. IVUS (6 F, 12.5 MHz probe or 10 F 9 MHz) coupled with fluoroscopy for the placement of radiopaque markers was used for target site identification, landing zone measurement, device positioning, and assessment of endovascular repair.

Results

Hospital mortality was 4/89 (4.5%). Number of devices implanted in each patient was 1.2 (range, 1–3). X-ray exposure time was 12 ± 8 minutes. Median procedure time was 63 ± 20 minutes. Conversion to open surgery was necessary in one patient (1.1%) because of aortic dissection. In nine patients (10.1%) left subclavian artery was covered because of a short neck. Two patients (2.2%) had vascular access lesions and required surgical repair. One patient developed paraplegia (1.1%). Early endoleak was observed in eight patients (8.9%) and 4 (4.5%) required additional procedures (proximal or distal extensions). Late conversion was necessary in one patient (1.1%).

Conclusions

IVUS provides all information necessary for device selection, target site identification as well as safe and correct deployment of thoracic endoprostheses and makes periprocedural angiography unnecessary, thus avoiding the risk of renal failure because of contrast medium.
The Current Status of Anastomotic Devices for Coronary Artery Bypass Surgery
Authors: Puskas John D.
Published: February 2009

The purpose of this article is to briefly review the history of proximal and distal anastomotic devices and to discuss presently available devices. Clinical outcome data from the EPIC Trial of the Cardica PAS-Port Proximal Anastomosis System will also be presented.
Linker histone H1 is essential for Drosophila development, the establishment of pericentric heterochromatin, and a normal polytene chromosome structure
Authors: Lu Xingwu , Wontakal Sandeep N. , Emelyanov Alexander V. , Morcillo Patrick , Konev Alexander Y. , Fyodorov Dmitry V. , Skoultchi Arthur I.
Published: February 2009

We generated mutant alleles of Drosophila melanogaster in which expression of the linker histone H1 can be down-regulated over a wide range by RNAi. When the H1 protein level is reduced to ∼20% of the level in wild-type larvae, lethality occurs in the late larval – pupal stages of development. Here we show that H1 has an important function in gene regulation within or near heterochromatin. It is a strong dominant suppressor of position effect variegation (PEV). Similar to other suppressors of PEV, H1 is simultaneously involved in both the repression of euchromatic genes brought to the vicinity of pericentric heterochromatin and the activation of heterochromatic genes that depend on their pericentric localization for maximal transcriptional activity. Studies of H1-depleted salivary gland polytene chromosomes show that H1 participates in several fundamental aspects of chromosome structure and function. First, H1 is required for heterochromatin structural integrity and the deposition or maintenance of major pericentric heterochromatin-associated histone marks, including H3K9Me2 and H4K20Me2. Second, H1 also plays an unexpected role in the alignment of endoreplicated sister chromatids. Finally, H1 is essential for organization of pericentric regions of all polytene chromosomes into a single chromocenter. Thus, linker histone H1 is essential in Drosophila and plays a fundamental role in the architecture and activity of chromosomes in vivo.
Interplay between ethylene, ETP1/ETP2 F-box proteins, and degradation of EIN2 triggers ethylene responses in Arabidopsis
Authors: Qiao Hong , Chang Katherine N. , Yazaki Junshi , Ecker Joseph R.
Published: February 2009

The gaseous plant hormone ethylene can trigger myriad physiological and morphological responses in plants. While many ethylene signaling pathway components have been identified and characterized, little is known about the function of the integral membrane protein ETHYLENE-INSENSITIVE2 (EIN2), a central regulator of all ethylene responses. Here, we demonstrate that Arabidopsis thaliana EIN2 is a protein with a short half-life that undergoes rapid proteasome-mediated protein turnover. Moreover, EIN2 protein accumulation is positively regulated by ethylene. We identified two F-box proteins, EIN2 TARGETING PROTEIN1 (ETP1) and EIN2 TARGETING PROTEIN2 (ETP2), that interact with the EIN2 C-terminal domain (EIN2-CEND), which is highly conserved and sufficient to activate most ethylene responses. Overexpression of ETP1 or ETP2 disrupts EIN2 protein accumulation, and these plants manifest a strong ethylene-insensitive phenotype. Furthermore, knocking down the levels of both ETP1 and ETP2 mRNAs using an artificial microRNA (amiRNA) leads to accumulation of EIN2 protein, resulting in plants that display constitutive ethylene response phenotypes. Finally, ethylene down-regulates ETP1 and ETP2 proteins, impairing their ability to interact with EIN2. Thus, these studies reveal that a complex interplay between ethylene, the regulation of ETP1/ETP2 F-box proteins, and subsequent targeting and degradation of EIN2 is essential for triggering ethylene responses in plants.
Into the blue: Gene duplication and loss underlie color vision adaptations in a deep-sea chimaera, the elephant sharkCallorhinchus milii
Authors: Davies Wayne L. , Carvalho Livia S. , Tay Boon-Hui , Brenner Sydney , Hunt David M. , Venkatesh Byrappa
Published: February 2009

The cartilaginous fishes reside at the base of the gnathostome lineage as the oldest extant group of jawed vertebrates. Recently, the genome of the elephant shark,Callorhinchus milii, a chimaerid holocephalan, has been sequenced and therefore becomes the first cartilaginous fish to be analyzed in this way. The chimaeras have been largely neglected and very little is known about the visual systems of these fishes. By searching the elephant shark genome, we have identified gene fragments encoding a rod visual pigment,Rh1, and three cone visual pigments, the middle wavelength-sensitive orRh2pigment, and two isoforms of the long wavelength-sensitive orLWSpigment,LWS1andLWS2, but no evidence for the two short wavelength-sensitive cone classes,SWS1andSWS2. Expression of these genes in the retina was confirmed by RT-PCR. Full-length coding sequences were used for in vitro expression and gave the following peak absorbances: Rh1 496 nm, Rh2 442 nm, LWS1 499 nm, and LWS2 548 nm. Unusually, therefore, for a deep-sea fish, the elephant shark possesses cone pigments and the potential for trichromacy. Compared with other vertebrates, the elephant shark Rh2 and LWS1 pigments are the shortest wavelength-shifted pigments of their respective classes known to date. The mechanisms for this are discussed and we provide experimental evidence that the elephant shark LWS1 pigment uses a novel tuning mechanism to achieve the short wavelength shift to 499 nm, which inactivates the chloride-binding site. Our findings have important implications for the present knowledge of color vision evolution in early vertebrates.
In Situ Investigation of Leaf Water Status by Portable Unilateral Nuclear Magnetic Resonance
Authors: Capitani Donatella , Brilli Federico , Mannina Luisa , Proietti Noemi , Loreto Francesco
Published: February 2009

A portable unilateral nuclear magnetic resonance (NMR) instrument was used to detect in field conditions the water status of leaves of herbaceous crops (Zea mays, Phaseolus vulgaris), mesophyllous trees (Populus nigra), and natural Mediterranean vegetation characterized by water-spending shrubs (Cistus incanus) and water-saving sclerophyllous trees (Quercus ilex). A good relationship was observed between NMR signal, leaf relative water content, and leaf transpiration in herbaceous leaves undergoing fast dehydration or slowly developing a drought stress. A relationship was also observed between NMR signal and water potential of Populus leaves during the development of a water stress and when leaves recovered from the stress. In the natural vegetation, the relationship between NMR signal and water status was found in Cistus, the species characterized by high transpiration rates, when measured during a drought stress period and after a rainfall. In the case of the sclerophyllous Quercus, the NMR signal, the relative water content, and the transpiration rate did not change at different leaf water status, possibly because a large amount of water is compartmentalized in cellular structures and macromolecules. The good association between NMR signal and relative water content was lost in leaves exposed for 24 h to dehydration or to an osmotic stress caused by polyethylene glycol feeding. At this time, the transverse relaxation time became longer than in leaves maintained under optimal water conditions, and two indicators of membrane damage, the ion leakage and the emission of products of membrane lipoxygenation [(Z)-3-hexenal, (Z)-3-hexenol, and (E)-2-hexenol], increased. These results taken all together give information on the physiological state of a leaf under a developing stress and show the usefulness of the NMR instrumentation for screening vegetation health and fitness in natural and cultivated conditions. It is concluded that the portable unilateral NMR instrument may be usefully employed in field conditions to monitor nondestructively the water status of plants and to assist agricultural practices, such as irrigation scheduling, to minimize stomatal closure and the consequent limitation to plant production.
Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome
Authors: Teachey David T. , Greiner Robert , Seif Alix , Attiyeh Edward , Bleesing Jack , Choi John , Manno Catherine , Rappaport Eric , Schwabe Dirk , Sheen Cecilia , Sullivan Kathleen E. , Zhuang Hongming , Wechsler Daniel S. , Grupp Stephan A.
Published: February 2009

We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second‐line therapy for patients with steroid‐refractory disease.
Hypertriglyceridaemia with bexarotene in cutaneous T cell lymphoma: the role of omega‐3 fatty acids
Authors: Musolino Antonino , Panebianco Michele , Zendri Enrico , Santini Marcello , Di Nuzzo Sergio , Ardizzoni Andrea
Published: February 2009

Bexarotene is approved for the treatment of cutaneous T cell lymphomas in patients refractory to at least one prior systemic therapy. Associated hypertriglyceridaemia requires monitoring, but can readily be managed with concomitant medication, such as fenofibrate. Here we report three cases of hypertriglyceridaemia secondary to bexarotene assumption, which was adequately managed with omega‐3 fatty acids. If fenofibate‐related side effects occur, or a statin is required to control low‐density lipoprotein‐cholesterol, omega‐3 fatty acids should be considered as a good alternative therapy to lower lipid levels during bexarotene treatment.
Association of genetic polymorphisms with interferon‐induced haematologic adverse effects in chronic hepatitis C patients
Authors: Wada M. , Marusawa H. , Yamada R. , Nasu A. , Osaki Y. , Kudo M. , Nabeshima M. , Fukuda Y. , Chiba T. , Matsuda F.
Published: February 2009

Summary. Interferon (IFN)‐based combination therapy with ribavirin has become the gold standard for the treatment of chronic hepatitis C virus infection. Haematologic toxicities, such as neutropenia, thrombocytopenia, and anaemia, however, frequently cause poor treatment tolerance, resulting in poor therapeutic efficacy. The aim of this study was to identify host genetic polymorphisms associated with the efficacy or haematologic toxicity of IFN‐based combination therapy in chronic hepatitis C patients. We performed comprehensive single nucleotide polymorphism detection in all exonic regions of the 12 genes involved in the IFN signalling pathway in 32 healthy Japanese volunteers. Of 167 identified polymorphisms, 35 were genotyped and tested for an association with the efficacy or toxicity of IFN plus ribavirin therapy in 240 chronic hepatitis C patients. Multiple logistic regression analysis revealed that low viral load, viral genotypes 2 and 3, and a lower degree of liver fibrosis, but none of the genetic polymorphisms, were significantly associated with a sustained virologic response. In contrast to efficacy, multiple linear regression analyses demonstrated that two polymorphisms (IFNAR110848‐A/G andSTAT24757‐G/T) were significantly associated with IFN‐induced neutropenia (P = 0.013 andP = 0.011, respectively). Thrombocytopenia was associated with theIRF7789‐G/A (P = 0.031). In conclusion, genetic polymorphisms in IFN signalling pathway‐related genes were associated with IFN‐induced neutropenia and thrombocytopenia in chronic hepatitis C patients. In contrast to toxicity, the efficacy of IFN‐based therapy was largely dependent on viral factors and degree of liver fibrosis.
Pathogen trafficking pathways and host phosphoinositide metabolism
Authors: Weber Stefan S. , Ragaz Curdin , Hilbi Hubert
Published: February 2009

Phosphoinositide (PI) glycerolipids are key regulators of eukaryotic signal transduction, cytoskeleton architecture and membrane dynamics. The host cell PI metabolism is targeted by intracellular bacterial pathogens, which evolved intricate strategies to modulate uptake processes and vesicle trafficking pathways. Upon entering eukaryotic host cells, pathogenic bacteria replicate in distinct vacuoles or in the host cytoplasm. Vacuolar pathogens manipulate PI levels to mimic or modify membranes of subcellular compartments and thereby establish their replicative niche. Legionella pneumophila, Brucella abortus, Mycobacterium tuberculosis and Salmonella enterica translocate effector proteins into the host cell, some of which anchor to the vacuolar membrane via PIs or enzymatically turnover PIs. Cytoplasmic pathogens target PI metabolism at the plasma membrane, thus modulating their uptake and antiapoptotic signalling pathways. Employing this strategy, Shigella flexneri directly injects a PI‐modifying effector protein, while Listeria monocytogenes exploits PI metabolism indirectly by binding to transmembrane receptors. Thus, regardless of the intracellular lifestyle of the pathogen, PI metabolism is critically involved in the interactions with host cells.
Educational level, coping, and psychological and physical aspects of quality of life in heart transplant candidates
Authors: Burker Eileen J. , Madan Alok , Evon Donna , Finkel Jerry B. , Mill Michael R.
Published: February 2009

Abstract: Objective:  To determine whether demographic factors and coping strategies are related to quality of life in heart transplant candidates.

Method:  Participants were 50 inpatients being evaluated for heart transplant. Coping was measured using the COPE Inventory (1) (J Pers Soc Psychol, 56, 1989, 267). Quality of life was assessed using the SF‐36 (2) (Health Survey: Manual and Interpretation Guide, Quality Metric Inc, Lincoln, RI, 2000).

Results:  Higher education and less seeking of social support were independently associated with better physical functioning. Higher use of denial was associated with poorer mental health functioning.

Conclusions:  In patients with significant physical limitations, years of education appears to be protective. Less seeking of social support was associated with better physical functioning perhaps because individuals who feel better physically do not feel the need to elicit support. Alternatively, the tendency to not seek assistance could stem from personality characteristics such as avoidance or optimism. Denial was associated with worse mental health functioning. Denying the existence of a stressor may be a high risk coping strategy for patients who are pre‐transplant and even more dangerous for those who are post‐transplant given the need to be alert to symptoms. Proactive identification of patients at risk for poorer quality of life will allow for more timely psychosocial interventions, which could impact post‐transplant outcomes.
Development of an activity of daily living scale for patients with COPD: The Activity of Daily Living Dyspnoea scale
Authors: YOZA Yoshiyasu , ARIYOSHI Koya , HONDA Sumihisa , TANIGUCHI Hiroyuki , SENJYU Hideaki
Published: February 2009

Background and objective:  Patients with COPD often experience restriction in their activities of daily living (ADL) due to dyspnoea. This type of restriction is unique to patients with COPD and cannot be adequately evaluated by the generic ADL scales. This study developed an ADL scale (the Activity of Daily Living Dyspnoea scale (ADL‐D scale)) for patients with COPD and investigated its validity and internal consistency.

Methods:  Patients with stable COPD were recruited and completed a pilot 26‐item questionnaire. Patients also performed the Incremental Shuttle Walk Test (ISWT), and completed the St. George's Respiratory Questionnaire (SGRQ) and Medical Research Council (MRC) dyspnoea grade.

Results:  There were 83 male participants who completed the pilot questionnaire. Following the pilot, eight items that were not undertaken by the majority of subjects, and three items judged to be of low clinical importance by physical therapists were removed from the questionnaire. The final ADL‐D scale contained 15 items. Scores obtained with the ADL‐D scale were significantly correlated with the MRC dyspnoea grades, distance walked on the ISWT and SGRQ scores. The ADL‐D scores were significantly different across the five grades of the MRC dyspnoea grade. The ADL‐D scale showed high consistency (Chronbach's α coefficient of 0.96).

Conclusions:  The ADL‐D scale is a useful scale for assessing impairments in ADL in Japanese male patients with COPD.
Small airways obstruction syndrome in clinical practice
Authors: CHEN Chiung‐Zuei , LIN Chien‐Chung , LEE Cheng‐Hung , CHANG Han‐Yu , HSIUE Tzuen‐Ren
Published: February 2009

Background and objective:  Small airways obstruction syndrome (SAOS) is a particular pulmonary function test (PFT) pattern showing decreased VC and FEV1 but a normal FEV1/VC ratio and TLC. The significance of this syndrome in clinical practice has not been comprehensively investigated.

Methods:  This study retrospectively identified all patients who had performed PFT that showed a SAOS pattern at a university teaching hospital over 1 year. A simple algorithm for differential diagnosis was developed and validated.

Results:  Of the 3207 PFT performed, 153 (4.8%) showed a pattern indicating SAOS. Among these, a final diagnosis was confirmed for 85 (63.4%) of the patients. The causes of SAOS included both restrictive and obstructive lung diseases with the leading causes being early interstitial lung disease (n = 20; 23.3%), chest wall deformity (n = 12; 14.1%) and asthma (n = 10; 11.6%). Using a cut‐off point of TLC of <95% predicted value to identify restrictive ventilatory defects (P = 0.002) and of ≥95% predicted combined with RV/TLC ≥55% to identify obstructive ventilatory defects (P < 0.001), a simplified algorithm with good accuracy (86.6%) was identified. Validation in an independent group showed accuracy of 91%.

Conclusions:  The PFT pattern called SAOS is not uncommon. The most common causes of SAOS were early interstitial lung disease, chest wall deformity and asthma. A diagnostic algorithm was proposed, which may help physicians' decision‐making in their daily practice.
Chronic intranasal administration of Aspergillus fumigatus spores leads to aggravation of airway inflammation and remodelling in asthmatic rats
Authors: GAO Fu‐Sheng , QIAO Jian‐Ou , ZHANG Yi , JIN Xian‐Qiao
Published: February 2009

Background and objective:  Epidemiological evidence indicates a close link between exposure to fungi and deterioration of asthma. However, the role of fungi as an exogenous precipitant for initiation and progression of asthma has been incompletely explored. In this study, the effects of Aspergillus fumigatus exposure on airway inflammation and remodelling in a rat model of chronic asthma were investigated.

Methods:  The rat model of chronic asthma was established by systemic sensitization and repeated challenge with ovalbumin (OVA). The asthmatic rats were exposed to chronic intranasal inhalation of A. fumigatus spores. Changes in airway inflammation, remodelling and BHR were measured after exposure to the fungus.

Results:  Chronic inhalation of A. fumigatus spores elevated the production of T helper 2 (Th2) cytokines, increased the concentration of total serum IgE, and resulted in the recruitment of eosinophils and lymphocyte infiltration into the airways of asthmatic rats. Goblet cell hyperplasia, mucus hyperproduction and subepithelial collagen deposition were also induced by inhalation of the fungus. The remodelling changes induced by inhalation of the fungus paralleled the changes in BHR in this rat model of asthma.

Conclusions:  Chronic exposure to A. fumigatus aggravated Th2 airway inflammation, promoted airway remodelling and increased BHR in OVA‐sensitized and ‐challenged rats.
Road ahead to respiratory health: Experts chart future research directions
Authors: HEFFNER John E. , HOLGATE Stephen T. , CHUNG Kian Fan , NIEDERMAN Michael S. , DALEY Charles L. , JETT James R. , STRADLING John R. , WELLS Athol U. , LIGHT Richard W. , TAPSON Victor F. , HANSELL David M. , PROVONOST Peter J. , LEE Y.C. Gary
Published: February 2009

Respiratory illnesses are a huge and rising burden to health‐care systems and societies worldwide. Research is crucial to tackle the enormous problem of chest diseases. However the vast number of research questions and available research approaches often creates confusion and risks dilution of resources by spreading them too diffusely. Clear research directions will help to use research funds efficiently to provide treatment advances that benefit patient care. This paper presents the visions of leading experts on future research directions, focusing on what should rather than what is going to be done. These opinions provide a guide for new investigators and a platform for intellectual debates through which coordinated research efforts can help progress towards respiratory health.
The role of cytoreductive nephrectomy in the era of molecular targeted therapy
Authors: Polcari Anthony J , Gorbonos Alex , Milner John E , Flanigan Robert C
Published: February 2009

While the widespread use of imaging has resulted in an increasing number of incidentally detected renal cancers, up to one third of patients present with metastatic disease and a significant number of those with clinically localized disease subsequently develop metastasis. The prognosis for patients with metastatic disease has traditionally been poor, with a 2‐year survival of only 10 to 20%. However, over the past decade a number of developments have enhanced the treatment of these patients. Phase III trials have demonstrated a significant improvement in overall survival for well‐selected patients undergoing cytoreductive nephrectomy prior to immunotherapy. Meanwhile, the recent introduction of molecular targeted agents has resulted in improved response rates and tolerability compared with immunotherapy, and has prompted a re‐evaluation of the role and timing of surgery in patients with advanced disease. This review examines the role of surgical therapy for patients with metastatic disease in the new era of molecular targeted therapy.
Fluid control in elderly patients with nocturia
Authors: Natsume Osamu , Kaneko Yoshiteru , Hirayama Akihide , Fujimoto Kiyohide , Hirao Yoshihiko
Published: February 2009

Objectives:  To investigate the pathophysiology of nocturnal polyuria associated with aging.

Methods:  Fifty patients (mean age 67.7 years, range 50–87) with nocturia were recruited for this prospective study. Patients were classified into nocturnal polyuria (NP) and non‐nocturnal polyuria (non‐NP) groups based on records of their frequency‐volume charts. A hypertonic saline infusion test was carried out to evaluate individual osmotic and volume control.

Results:  In the NP group, there was a significantly increased nocturnal diuretic rate compared with the daytime diuretic rate. In the non‐NP group, there was a significantly decreased nocturnal diuretic rate compared with the daytime rate. There was also a positive correlation between systolic blood pressure and nocturnal diuretic rate, and a negative correlation between systolic blood pressure and daytime diuretic rate in those with NP, but no correlation in those without NP. Thus, a close relationship between diuretic rates and systolic blood pressure was seen in NP patients. Moreover, a slight overall shift upward from the physiological range of plasma osmolality relative to arginine vasopressin after hypertonic saline loading was seen in those with NP compared with those without. An altered circadian rhythm was also seen in diurnal plasma arginine vasopressin levels in patients with and without NP.

Conclusions:  Patients with nocturnal polyuria are likely to have a more hypervolemic or vasoconstrictive condition. It is considered that non‐osmotic control takes on a greater meaning in patients with nocturnal polyuria, though osmotic control contributes less to diuresis within the physiological plasma osmolality range with aging.
Comparison of serum HER2/neu with immunohistochemical HER2/neu expression for the prediction of biochemical progression in metastatic prostate cancer
Authors: Tambo Mitsuhiro , Higashihara Eiji , Terado Yuichi , Nutahara Kikuo , Okegawa Takatsugu
Published: February 2009

Objectives:  To examine whether pretreatment serum human epidermal growth factor receptor 2 (HER2/neu) and immunohistochemical HER2/neu expression predict biochemical recurrence‐free survival in advanced prostate cancer.

Methods:  We studied 75 untreated patients with metastatic prostate cancer and compared them to a control group of 97 patients without histologically diagnosed prostate cancer. Serum samples were collected for HER2/neu protein analysis before the patients started endocrine therapy. HER2/neu expression in the prostate tissue was evaluated using immunohistochemical analysis.

Results:  Serum concentration of HER2/neu in patients with prostate cancer was significantly higher than in those without cancer (P = 0.005). Based on the median HER2/neu value, a cut‐off level of 12.5 ng/mL was established to separate low from high serum HER2/neu levels. The biochemical recurrence‐free survival rate was significantly lower in patients with a high serum HER2 level (P < 0.001). HER2/neu overexpression was found in 18 patients (24%) by immunohistochemical analysis. Biochemical recurrence‐free survival rates did not show a statistically significant difference between HER2/neu positive and negative groups. Multivariate analysis showed that the pretreatment serum HER2/neu value was an independent predictor of biochemical recurrence (P = 0.02).

Conclusions:  Pretreatment serum HER2/neu may represent a more valuable tool than immunohistochemical HER2/neu expression for the prediction of biochemical recurrence in metastatic prostate cancer patients.
Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options
Authors: Ludolph A. C. , Kassubek J. , Landwehrmeyer B. G. , Mandelkow E. , Mandelkow E.‐M. , Burn D. J. , Caparros‐Lefebvre D. , Frey K. A. , De Yebenes J. G. , Gasser T. , Heutink P. , Höglinger G. , Jamrozik Z. , Jellinger K. A. , Kazantsev A. , Kretzschmar H. , Lang A. E. , Litvan I. , Lucas J. J. , McGeer P. L. , Melquist S. , Oertel W. , Otto M. , Paviour D. , Reum T. , Saint‐Raymond A. , Steele J. C. , Tolnay M. , Tumani H. , Van Swieten J. C. , Vanier M. T. , Vonsattel J.‐P. , Wagner S. , Wszolek Z. K. ,   for the Reisensburg Working Group for Tauopathies With Parkinsonism
Published: February 2009

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease‐modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann‐Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson–dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.
Detection of Rare Nonsynonymous Variants in TGFB1 in Otosclerosis Patients
Authors: Thys M. , Schrauwen I. , Vanderstraeten K. , Dieltjens N. , Fransen E. , Ealy M. , Cremers C. W. R. J. , Van De Heyning P. , Vincent R. , Offeciers E. , Smith R. H. , Van Camp G.
Published: February 2009

Otosclerosis is one of the most common forms of hearing loss in the European population. We have identified a SNP in the TGFB1 (transforming growth factor beta 1) gene that is associated with susceptibility to otosclerosis. The protective allele of this variant, with isoleucine at position 263 of the protein, is more biologically active than the risk allele, which has a threonine in this position. Because recent studies have shown that not only common, but also rare variants can be involved in complex diseases, we performed DNA sequence analysis of the exons and intron‐exon boundaries of TGFB1 in 755 otosclerosis patients and 877 control samples. We found 3 different nonsynonymous variants (E29, A29 and I241) in four otosclerosis patients, but no such changes were found in controls. In silico analysis shows that these variations could influence TGF‐β1 function and activity. Taking into account that most rare missense alleles are thought to have a biological effect, the data suggest that multiple rare amino acid changing variants in TGF‐β1 may contribute to susceptibility to otosclerosis.
Robust Tests for Single‐marker Analysis in Case‐Control Genetic Association Studies
Authors: Li Qizhai , Zheng Gang , Liang Xueying , Yu Kai
Published: February 2009

Choosing an appropriate single‐marker association test is critical to the success of case‐control genetic association studies. An ideal single‐marker analysis should have robust performance across a wide range of potential disease risk models. MAX was designed specifically to achieve such robustness. In this work, we derived the power calculation formula for MAX and conducted a comprehensive power comparison between MAX and two other commonly used single‐marker tests, the one‐degree‐of‐freedom (1‐df) Cochran‐Armitage trend test and the 2‐df Pearson χ2 test. We used a single‐marker disease risk model and a two‐marker haplotype risk model to explore the performances of the above three tests. We found that each test has its own “sweet” spots. Among the three tests considered, MAX appears to have the most robust performance.
Rapid infusion of rituximab over 60 min
Authors: Tuthill Mark , Crook Tim , Corbet Tim , King Jenny , Webb Andrew
Published: February 2009

The use of rituximab is increasing and regular administration over 2 to 3 h requires considerable healthcare resources and is inconvenient for patients. There is interest in reducing rituximab administration times and although infusion of rituximab over 90 min is safe, there is limited data on the safety of 60 min infusions. We recently changed our second and subsequent rituximab infusion protocol to a 60 min constant rate infusion for patients who had no significant reaction to their first infusion and conducted a prospective safety audit. Fifty‐four patients aged between 20 and 86 received 105 rapid 60‐min‐rituximab infusions without any significant infusion reactions. We also conducted a survey of 20 major cancer centres in the UK and asked about their local rituximab administration policy. We found that 70% are using 90 min rituximab infusion protocols and that 25% are using slower rate infusions. Only one surveyed unit (5%) was using a 60 min rituximab infusion protocol. This study shows that rapid rituximab infusions over 60 min is safe and can be considered for most patients. This finding has considerable beneficial service implications for patients and healthcare providers and shows that there is considerable scope for further reduction in rituximab administration times within the UK.
Molecular Docking and 3D QSAR Studies of Chk2 Inhibitors
Authors: Pasha Fahran Ahmad , Muddassar Muhammad , Joo Cho Seung
Published: February 2009

Isothiazole‐carboxamidines are potent ATP competitive checkpoint kinases (Chk2) inhibitors. Three‐dimensional quantitative structure–activity relationship models were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. The study was performed using three different geometrical methods. In geometrical method‐1, molecules were fully optimized by PM3 Hamiltonian and aligned using common substructure. This alignment was subsequently used for Ligand‐based comparative molecular field analysis and comparative molecular similarity indices analysis. In receptor‐guided analyses, the receptor coordinates were obtained from public domine (PDB 2cn8). The molecule‐7 was docked into receptor protein using FlexX and two plausible binding modes were identified. These modes were used as templates for geometrical method‐2 and 3. These methods were used for 3D QSAR. The geometrical method‐3‐based comparative molecular field analysis (q 2 = 0.75, r 2 = 0.87 and r 2predict = 0.81) and comparative molecular similarity indices analysis (q 2 = 0.90, r 2 = 0.96 and r 2predict = 0.75) gave better result. The steric, hydrophobic and hydrogen bond donor fields effects significantly contribute to activity. In this way, the receptor‐guided study presents a more detailed understanding about chk2 active site interactions. The study indicated some modifications to the active molecule which might be valuable to improve the activity.
Cytostatic and Antiviral Activity Evaluations of Hydroxamic Derivatives of Some Non‐steroidal Anti‐inflammatory Drugs
Authors: Rajic Zrinka , Butula Ivan , Zorc Branka , Kraljevic Pavelic Sandra , Hock Karlo , Pavelic Kresimir , Naesens Lieve , De Clercq Erik , Balzarini Jan , Przyborowska Monika , Ossowski Tadeusz , Mintas Mladen
Published: February 2009

Non‐steroidal anti‐inflammatory drugs (NSAID) pharmacophores are interesting in designing potential anticancer drugs. Indeed, numerous experimental, epidemiologic and clinical studies suggest that NSAIDs are promising anticancer drugs. Herein, NSAID hydroxamic acids 3a‐i were prepared by a new synthetic procedure and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts (WI38). Antiviral activity evaluation results indicated that 3f had only a minor activity against the influenza virus A/H1N1 subtype with a selectivity index of 7–10. On the other hand, the results of thein vitrocytostatic activity evaluations revealed that the majority of NSAID hydroxamic acid derivatives3a–iexhibited a strong non‐specific antiproliferative effect at the highest concentration (100 μm) on the tested cell line panel. Only compounds3b,3eand3iexerted a differential dose‐dependent inhibitory activity against the growth of HeLa cells (p < 0.05) at concentration 10 μm. Among those three compounds, only compound3bshowed a selective cytostatic effect on HeLa in comparison with normal fibroblasts.
Synthesis, Structural Characterization and Biological Evaluation of Novel Stilbene Derivatives as Potential Antimalarial Agents
Authors: Jung Mankil , Park Won‐Hwan , Jung Jae‐Chul , Lim Eunyoung , Lee Yongnam , Oh Seikwan , Moon Hyung‐In
Published: February 2009

A series of benzamide‐containing stilbene derivatives was synthesized through the incorporation of short basic side‐chains in the B‐ring hydroxy position of resveratrol. Their antiplasmodial activity was evaluated in vitro against the chloroquine resistant Plasmodium falciparum D10 strain, showing IC50 values between 1.5 and 80 μm, while their cytotoxicity was assessed using an human myeloid leukemia (U‐937) cell line. With a selectivity ratio of >51.02, the most selective of these derivatives, 29, also had the most lowest cytotoxic activity of the series.
Synthesis and Anticonvulsant Activity of 6‐Alkoxy‐[1,2,4]Triazolo[3,4‐a]Phthalazines
Authors: Zhang Lei , Guan Li‐Ping , Sun Xian‐Yu , Wei Cheng‐Xi , Chai Kyu‐Yun , Quan Zhe‐Shan
Published: February 2009

A new series of 6‐alkoxy‐[1,2,4]triazolo[3,4‐a]phthalazines (3a–3v) were synthesized and their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock test and the rotarod test respectively. Significant anticonvulsant activity was displayed by a number of compounds. The most promising compounds 6‐(4‐chlorobenzyloxy)‐[1,2,4]triazolo[3,4‐a]phthalazine (3f) and 6‐heptyloxy‐[1,2,4]triazolo[3,4‐a]phthalazine (3s) showed a median effective dose of 7.1 and 11.0 mg/kg, and had protective index value of 5.2 and 8.0 respectively. The two compounds were further found to have potent activity against seizures induced by pentylenetetrazole, isoniazid, thiosemicarbazide, 3‐mercaptopropionic acid but not seizures induced by strychnine, indicating that the two compounds might function by enhancing gamma‐aminobutyric acid neurotransmission.
Synthesis of Some N, N′‐Diacylhydrazine Derivatives with Radical‐Scavenging and Antifungal Activity
Authors: Liu Xing‐Hai , Shi Yan‐Xia , Ma Yi , He Guo‐Rong , Dong Wei‐Li , Zhang Chuan‐Yu , Wang Bao‐Lei , Wang Su‐Hua , Li Bao‐Ju , Li Zheng‐Ming
Published: February 2009

A series of N,N′‐diacylhydrazines were prepared and their structures were confirmed by 1H NMR, MS and FTICR‐MS. They were tested radical‐scavenging activity in vitro. The preliminary bioassays of title compounds showed that two compounds had excellent radical‐scavenging activity comparable with vitamin C, while the activity is highly relative to the substituents. Surprisingly, several compounds also exhibit favorable fungicidal activities. To further explore the comprehensive structure–activity relationships about the fungicidal activity, a three‐dimensional quantitative structure–activity relationship analysis using the method of comparative molecular field analysis was performed.
Binding Estimation after Refinement, a New Automated Procedure for the Refinement and Rescoring of Docked Ligands in Virtual Screening
Authors: Rastelli Giulio , Degliesposti Gianluca , Del Rio Alberto , Sgobba Miriam
Published: February 2009

Binding estimation after refinement (BEAR) is a novel automated computational procedure suitable for correcting and overcoming limitations of docking procedures such as poor scoring function and the generation of unreasonable ligand conformations. BEAR makes use of molecular dynamics simulation followed by MM‐PBSA and MM‐GBSA binding free energy estimates as tools to refine and rescore the structures obtained from docking virtual screenings. As binding estimation after refinement relies on molecular dynamics, the entire procedure can be tailored to the needs of the end‐user in terms of computational time and the desired accuracy of the results. In a validation test, binding estimation after refinement and rescoring resulted in a significant enrichment of known ligands among top scoring compounds compared with the original docking results. Binding estimation after refinement has direct and straightforward application in virtual screening for correcting both false‐positive and false‐negative hits, and should facilitate more reliable selection of biologically active molecules from compound databases.
A Forward Chemical Screen Using Zebrafish Embryos with Novel 2‐Substituted 2H‐Chromene Derivatives
Authors: Torregroza Ingrid , Evans Todd , Das Bhaskar C.
Published: February 2009

We synthesized 2‐substituted 2H‐chromene derivatives from salicylaldehyde using potassium vinylic borates in the presence of secondary amines. Our goal was to generate novel compounds that might modulate transforming growth factor‐β signaling, based on limited rational design. Potassium vinyl trifluoroborates react with salicylaldehydes at 80 °C in the presence of a secondary amine and produce 2‐substituted 2H‐chromene derivatives with a 70–90% yield. A small library of these compounds, predicted to potentially interact with transforming growth factor‐β receptors, was screened for bioactivity in living zebrafish embryos. We found that the related compounds differentially affect development, and demonstrate one compound that produces severe body axis alterations in early embryogenesis and at lower doses affects specifically cardiovascular development. This compound modulates specifically a Smad‐independent transforming growth factor‐β‐regulated mitogen‐activated protein kinase pathway, namely p‐SAPK/JNK. These compounds, as suggested by our biological assays, may prove useful to manipulate developmental programs and develop therapeutic tools.
Improving the oral health of older people in long‐term residential care: a review of the literature
Authors: Miegel Karen , Wachtel Tracey
Published: February 2009

Background.  Unrefutable evidence now links poor oral health with the development of preventable systemic illnesses and debilitating conditions that threaten quality of life and life itself. This is especially significant for an increasing older population who are dependent on others for care.

Aims and objectives.  The majority of studies analysing the oral health of older dependent people in long‐term residential care have been undertaken by dental professionals. This critical literature review examines the issue from a nursing perspective because nursing care providers have a fundamental role in daily oral health provision for dependent residents.

Conclusions.  Multiple barriers were found to negatively impact on daily oral healthcare provision, including lack of care provider education, oral health values, availability of resources, implementation of supportive policies, documentation and oral health assessment tools.

Relevance to clinical practice.  The nursing profession, at all levels, must become pro‐active in removing financial, political and workforce barriers that impact negatively on oral health outcomes. A multi‐faceted approach is required to address these barriers, including development and implementation of oral health education programmes, assessment screening tools, care plans, documentation, supply of oral hygiene aids and the appointment of oral care ‘champions’.
Arsenic‐trioxide‐induced apoptosis of chronic lymphocytic leukemia cells
Authors: BAIREY O. , VANICHKIN A. , SHPILBERG O.
Published: February 2009

Chronic lymphocytic leukemia (CLL) cells are characterized by defective apoptosis which leads to their extended survival. Arsenic trioxide (As2O3) was reported to induce cell death in many malignant cells, but the specific pathway of As2O3‐induced apoptosis/necrosis remains controversial. Our aim was to determine if As2O3 kills CLL cells through apoptosis and whether this is accompanied by reduction in Bcl‐2 levels. Cells from nine patients with CLL were incubated with increasing concentrations of As2O3 (0.5–2 μm) for 2, 7, or 14 days. Cells viability was measured using Alamar Blue assay and apoptosis using human Annexin V‐FITC and propidium iodine (PI) kit (BMS306FI; Bender MedSystems, Vienna, Austria). Intracellular Bcl‐2, Bax, and caspase‐3 levels were measured by flow cytometry. As2O3 significantly reduced CLL cell viability (P < 0.01) and induced apoptotic cell death in a time‐ and dose‐dependent manner. After 7 days, CLL cells showed a significant decrease in mean fluorescence intensity (MFI) of Bcl‐2 on flow cytometry study. Bax and caspase‐3 levels showed significant decrease in MFI only after prolonged incubations (7 and 14 days) and mostly at higher concentrations of As2O3. The mechanism underlying the reduction in viability of CLL cells incubated with As2O3 is mediated by induction of apoptosis maybe through the down‐regulation of Bcl‐2. Further studies are needed to elucidate the potential therapeutic role of As2O3 in CLL.
Raman tweezers sorting of single microbial cells
Authors: Huang Wei E. , Ward Andrew D. , Whiteley Andrew S.
Published: February 2009

We have selectively isolated microbial cells by identifying and then manipulating cells using a combination of Raman microspectroscopy and optical trapping. The criterion for cell discrimination is based on spectral peak shifts within the Raman spectrum of individual cells. A specific shift in the phenylalanine peak position from 1001 rel. cm−1 to 965 rel. cm−1 is utilized to indicate the uptake of 13C within the cell that utilized 13C‐substrate. Cells were captured and manipulated using an infrared (1064 nm) laser while Raman spectra were acquired over shorter timescales (30 s) using a co‐aligned 514.5 nm laser beam. Selected cells were manoeuvred to a clean part of a capillary tube and the tubes were cleaved to physically separate the cells. The technique was tested for cell viability and cross‐contamination effects using 70 single yeast cells (Saccharomyces cerevisia). Following these tests, 58 single bacterial cells (Escherichia coli DH5α, and Pseudomonas fluorescens SBW25::Km‐RFP) that exhibited 13C uptake were sorted from bacterial populations. Among those isolated cells, 11 out of 18 yeast cells and 7 out of 18 single SBW25::Km‐RFP cells were recovered by incubation; 2 out of 7 sorted yeast cells and 3 out of 8 sorted bacterial cells (single SBW25::Km‐RFP) were genome amplified correctly. We show that the Raman tweezers approach has the potential to open a new frontier to study unculturable microorganisms, which account for more than 99% microbes in natural environment.
Bacterial diversity associated with freshwater zooplankton
Authors: Grossart Hans‐Peter , Dziallas Claudia , Tang Kam W.
Published: February 2009

Bacterial community compositions (BCC) associated with the cladoceran Bosmina coregoni and the cyclopoid copepod Thermocyclops oithonoides in oligotrophic Lake Stechlin versus eutrophic Lake Dagow (northeastern Germany) were compared using molecular techniques. We also transplanted the zooplankton from their native lake to the other lake, and studied changes in their associated BCC as a result of the modified ambient environment. Bacterial community composition associated with B. coregoni was quite conservative between the oligotrophic and eutrophic lakes, and most of the bacteria belonged to Alpha‐ and Betaproteobacteria. In contrast, BCC associated with T. oithonoides was highly variable and dependent on the environment, and Betaproteobacteria and Bacteroidetes were the most represented among the bacteria. Thermocyclops oithonoides from the oligotrophic lake was more able to retain its bacteria after being transplanted to the eutrophic lake than vice versa. This suggests that bacteria in oligotrophic water were more firmly attached to the copepod and better in resisting environmental fluctuations than those in eutrophic water.