bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure and Function of Vertebrate Metallothioneins
Authors: Hidalgo Juan , Chung Roger , Penkowa Milena , Vašák Milan
Published: March 2009

In 1957, Margoshes and Vallee reported on the isolation of a protein from horse kidney, which showed a high affinity for cadmium, and soon thereafter the protein was named metallothionein (MT) by the leading scientists Kägi and Vallee. Fifty years of intense research has dissected out many of the biochemical, molecular, and genetic aspects of these proteins, yet not that much is understood on its physiological putative functions. Being a highly conserved family of proteins would suggest essential biological functions, but these may be dispensable and/or assumed by other proteins as demonstrated by the phenotype of knock-out mice in normal conditions. Nevertheless, under challenging conditions (such as tissue injury) a strong phenotype appears that is suggestive of important physiological functions. This has been particularly well shown in the brain, where antiinflammatory, antioxidant and antiapoptotic effects of MT have been demonstrated. To date, the results gathered strongly support a therapeutic value of these proteins that deserve attention in clinical studies.
Auditory Evoked Potentials and Cochlear Implants: Research Findings and Clinical Applications in Children
Authors: Purdy Suzanne C , Gardner-Berry Kirsty
Published: March 2009

Auditory evoked potentials can be used to objectively assess hearing sensitivity, central auditory processing, and neural encoding of speech sounds up to the level of the auditory cortex. Evoked potentials have been of interest to clinicians and researchers in the cochlear implant field for a long time because of their potential for objectively predicting cochlear implant outcomes, as well as improving candidacy determination, and implant programming. Neural response telemetry and intra-operative electrical auditory brainstem recording have been routinely performed by implant programs for many years. Recently, there has been great interest in potential clinical applications of cortical auditory evoked potentials in the implant field. Research and clinical applications are reviewed and case studies are presented that illustrate clinical applications of cortical evoked potentials in children before and after implantation.
Intradot dynamics of InAs quantum dot based electroabsorbers
Authors: Piwonski Tomasz , Pulka Jaroslaw , Madden Gillian , Huyet Guillaume , Houlihan John , Viktorov Evgeny A. , Erneux Thomas , Mandel Paul
Published: March 2009

The carrier relaxation and escape dynamics of InAs/GaAs quantum dot waveguide absorbers is studied using heterodyne pump-probe measurements. Under reverse bias conditions, we reveal differences in intradot relaxation dynamics, related to the initial population of the dots’ ground or excited states. These differences can be attributed to phonon-assisted or Auger processes being dominant for initially populated ground or excited states, respectively.
Enhanced spin injection and detection in spin valves with integrated tunnel barriers
Authors: Vogel Andreas , Wulfhorst Jeannette , Meier Guido
Published: March 2009

We study the spin-dependent transport in lateral spin-valve devices with aluminum oxide tunnel barriers at the interfaces between NiFe electrodes and an interconnecting Al strip. Different total conductivities per cross-sectional area are achieved by varying the oxygen pressure, the oxidation time, and the thickness of the oxidized aluminum layer. The experimental data are consistent with our theoretical description including spin diffusion, spin relaxation, and tunnel barriers at the interfaces between electrodes and aluminum strip. With decreasing tunnel conductance the amplitude of the nonlocal spin-valve effect increases by two orders of magnitude up to saturation.
A UV-sensitive syndrome patient with a specific
CSA
mutation reveals separable roles for CSA in response to UV and oxidative DNA damage
Authors: Nardo Tiziana , Oneda Roberta , Spivak Graciela , Vaz Bruno , Mortier Laurent , Thomas Pierre , Orioli Donata , Laugel Vincent , Stary Anne , Hanawalt Philip C. , Sarasin Alain , Stefanini Miria
Published: March 2009

UV-sensitive syndrome (UV
S
S) is a recently-identified autosomal recessive disorder characterized by mild cutaneous symptoms and defective transcription-coupled repair (TC-NER), the subpathway of nucleotide excision repair (NER) that rapidly removes damage that can block progression of the transcription machinery in actively-transcribed regions of DNA. Cockayne syndrome (CS) is another genetic disorder with sun sensitivity and defective TC-NER, caused by mutations in the
CSA
or
CSB
genes. The clinical hallmarks of CS include neurological/developmental abnormalities and premature aging. UV
S
S is genetically heterogeneous, in that it appears in individuals with mutations in
CSB
or in a still-unidentified gene. We report the identification of a UV
S
S patient (UV
S
S1VI) with a novel mutation in the
CSA
gene (p.trp361cys) that confers hypersensitivity to UV light, but not to inducers of oxidative damage that are notably cytotoxic in cells from CS patients. The defect in UV
S
S1VI cells is corrected by expression of the WT
CSA
gene. Expression of the p.trp361cys-mutated
CSA
cDNA increases the resistance of cells from a CS-A patient to oxidative stress, but does not correct their UV hypersensitivity. These findings imply that some mutations in the
CSA
gene may interfere with the TC-NER-dependent removal of UV-induced damage without affecting its role in the oxidative stress response. The differential sensitivity toward oxidative stress might explain the difference between the range and severity of symptoms in CS and the mild manifestations in UV
s
S patients that are limited to skin photosensitivity without precocious aging or neurodegeneration.
Infrapopliteal angioplasty with a long over-the-wire (OTW) balloon in the treatment of severe limb ischemia in diabetic patients: A retrospective study
Authors: Wang Jue , Zhu Yue-Qi , Zhao Jun-Gong , Wang Jian-Bo , Cheng Ying-Sheng , Li Ming-Hua , Wang Wu , Zhang Pei-Lei , Du Zhuo-Ying
Published: March 2009

Background: The use of short balloons in the treatment of infrapopliteal arterial occlusive disease in diabetic patients often has a poor clinical outcome.

Purpose: To retrospectively evaluate the safety and efficacy of a long over-the-wire (OTW) balloon as a primary percutaneous transluminal angioplasty (PTA) treatment for diabetic infrapopliteal severe limb ischemia.

Material and Methods: Infrapopliteal PTA with a long OTW balloon was performed between April 2007 and March 2008 in 34 patients (53 limbs), including a total of 119 lesions. Patient age was 71.8±7.4 years. All patients had limb ischemic symptoms. Angiography was retrospectively analyzed, and every lesion categorized and classified according to its length and severity. The mean follow-up period was 7.4±2.6 months. Lower-limb magnetic resonance angiography (MRA) was performed every 3 months during follow-up, and clinical data were collected.

Results: Altogether, 92% of patients were successfully treated. Ankle-brachial index (ABI) and transcutaneous oxygen tension (TcPO2) improved from 0.50±0.18 and 18.85±12.08 mmHg, respectively, before the procedure to 0.81±0.12 and 39.85±12.67 mmHg, respectively, after the procedure. At the end of follow-up, 29 patients had maintained a stable outcome. Five patients had symptom recurrence, and three of them underwent a second PTA. Two major amputations and four minor amputations were performed, with a 94% limb salvage rate and 59% patency rate.

Conclusion: Infrapopliteal PTA with a long OTW balloon was feasible, with encouraging midterm outcome, in the treatment of severe limb ischemia in diabetic patients in this single-center case series. Further research is warranted to evaluate long-term outcome.
The Myoendothelial Junction: Breaking through the Matrix?
Authors: HEBERLEIN KATHERINE R. , STRAUB ADAM C. , ISAKSON BRANT E.
Published: March 2009

Within the vasculature, specialized cellular extensions from endothelium (and sometimes smooth muscle) protrude through the extracellular matrix where they interact with the opposing cell type. These structures, termed myoendothelial junctions, have been cited as a possible key element in the control of several vascular physiologies and pathologies. This review will discuss observations that have led to a focus on the myoendothelial junction as a cellular integration point in the vasculature for both homeostatic and pathological conditions and as a possible independent signaling entity. We will also highlight the need for novel approaches to studying the myoendothelial junction in order to comprehend the cellular biology associated with this structure.
EU FOOD SAFETY POLICY
Authors: Holm Lotte , Halkier Bente
Published: March 2009

Food safety is a vital concern and a salient regulatory arena, with important implications for consumers, producers and retailers of food. Following the BSE crisis in 1996, and with the alleged aim to restore consumer confidence in food, national and fragmented food safety regulations across Europe were transformed into a new European-wide food regulatory system. This included a new legal and regulatory framework, a new institutional set-up of public authorities, and new roles for public and private actors. The article analyses how the division of responsibilities for food safety has changed both across the EU as a whole and, more specifically, in six European countries. Based on seven case studies, which were prepared as part of a comparative research project, TRUSTINFOOD, the article analyses how core principles of the new EU food safety policy was put into practice in Denmark, Germany, Italy, Norway, Portugal and the UK. The article demonstrates how changes in regulatory practices in EU and the six countries converge with respect to formal regulatory framework and diverge with respect to practical implementation and institutional reform. It is a shared perspective to restore consumer confidence by enhancing institutional independence, transparency and consumer agency, but conditions for this differ between the countries. The structure of food markets and the political agendas around food issues continue to vary in different national contexts but the new food safety policy may further the development of the single European market and thus promote changes within the food production systems in Europe.
Old and new biomarkers of heart failure
Authors: Emdin Michele , Vittorini Simona , Passino Claudio , Clerico Aldo
Published: March 2009

Heart failure (HF) may be considered as the fatal finishing line of all cardiovascular disorders. Despite advances in the understanding and treatment, it still has a poor prognosis. Heart failure is a syndrome, rather than a primary diagnosis, which results from any structural or functional cardiac disorder that impairs the ability of the heart to support the physiological circulation. This is sustained by a chronic imbalance in the neurohormonal control of circulation. Unfortunately, there is no single diagnostic test for HF, and the accuracy of diagnosis by clinical means only (i.e. a combination of history, physical examination and appropriate investigations) is often inadequate. Diagnosis and risk stratification depend on the availability of accurate, and effective markers of either risk or disease. There is an increasing interest in the development of new biomarkers, and a great number of laboratory tests have recently been proposed. The goals of this ‘commentary’ are to (i) briefly discuss the characteristics of an ideal HF biomarker; (ii) describe the analytical performance and clinical relevance of currently available biomarker assay methods, (iii) evaluate newer biomarkers and finally, (iv) design a scheme to optimize the search for efficient diagnostic and prognostic biomarkers for HF.
The development and evaluation of a three-dimensional, echo-integration method for estimating fish-school abundance
Authors: Nishimori Yasushi , Iida Kohji , Furusawa Masahiko , Tang Yong , Tokuyama Kozo , Nagai Sanae , Nishiyama Yoshihiro
Published: March 2009

Nishimori, Y., Iida, K., Furusawa, M., Tang, Y., Tokuyama, K., Nagai, S., and Nishiyama, Y. 2009. The development and evaluation of a three-dimensional, echo-integration method for estimating fish-school abundance. – ICES Journal of Marine Science, 66: 1037–1042. A three-dimensional, echo-integration method (3DEI) which uses scanning-sonar observations of a fish school to estimate its backscattering cross section (σbss = Nσbs) was developed. Coupled with a modelled estimate of the average backscattering cross section of individual fish (σbs), the 3DEI theoretically allows estimation of the number of fish in a school (N). To test the practicality of the method, measurements were made of a metal sphere simulating fish, and several spheres simulating a fish school. The 3DEI correctly measured the σbss of each target. Next, the 3DEI was applied to echo data from a herring school in the Norwegian Sea, to estimate its σbss. Several values of σbs were estimated with a prolate-spheroid model, each assuming different distributions of fish orientations relative to the sonar beam. Dividing the 3DEI-estimated σbss by these modelled σbs shows that the resulting estimates of N were closer to the skipper's estimate than those estimated using the apparent school volume. The 3DEI measurements of σbss, modelled σbs, and resulting accuracy of N depend largely on the assumed orientations of the fish relative to the acoustic beam.
Sponge-like structures for application in photovoltaics
Authors: Perlich Jan , Kaune Gunar , Memesa Mine , Gutmann Jochen S , Müller-Buschbaum Peter
Published: March 2009

Large surface areas at an interface between two different materials are desired in many research fields where the interaction between these materials significantly affects the performance of the physical system. This behaviour is illustrated on sponge-like structures, which assign for such a high surface area, and demonstrate the development from bulk material to thin films and a variety of applications. The focus is on sponge-like nanostructures consisting of a network of aggregated titania nanoparticles applied in hybrid structures for photovoltaics. Examples based on a sol–gel process for the preparation of titania nanostructures in thin films, mimicking the sponge morphology, are shown. In general, titania films are widely used in photovoltaics, contributing to a large surface area available for interfacial reactions, e.g. charge carrier transfer routes. Interpenetrating networks with dimensions matching exciton diffusion lengths in the polymer component of a hybrid organic–inorganic photovoltaic structure are highly desirable. To characterize the fabricated morphology, atomic force microscopy and field-emission scanning electron microscopy are employed in real space. The advanced scattering technique of grazing-incidence small-angle X-ray scattering complements the characterization in reciprocal space. From the obtained results, the sponge-like morphology is verified, a physical description of the morphology with statistical relevance is constructed and the successful complete filling of the network is shown. According to this description, the presented sponge-like titania nanostructures are well suited for use in hybrid organic–inorganic solar cells.
Self-healing behaviour in man-made engineering materials: bioinspired but taking into account their intrinsic character
Authors: van der Zwaag S , van Dijk N.H , Jonkers H.M , Mookhoek S.D , Sloof W.G
Published: March 2009

Man-made engineering materials generally demonstrate excellent mechanical properties, which often far exceed those of natural materials. However, all such engineering materials lack the ability of self-healing, i.e. the ability to remove or neutralize microcracks without (much) intentional human interaction. This inability is the unintentional consequence of thedamage preventionparadigm underlying all current engineering material optimization strategies. Thedamage managementparadigm observed in nature can be reproduced successfully in man-made engineering materials, provided the intrinsic character of the various types of engineering materials is taken into account.
The ‘prediction imperative’ as the basis for self-awareness
Authors: Llinás Rodolfo R. , Roy Sisir
Published: March 2009

Here, we propose that global brain function is geared towards the implementation of intelligent motricity. Motricity is the only possible external manifestation of nervous system function (other than endocrine and exocrine secretion and the control of vascular tone).

The intelligence component of motricity requires, for its successful wheeling, a
prediction imperative
to approximate the consequences of the impending motion.

We address how such predictive function may originate from the dynamic properties of neuronal networks.
Inferences about mental states
Authors: Mitchell Jason P.
Published: March 2009

Human social cognition relies on an ability to predict what others will think, feel or do in novel situations. Research in social neuroscience has consistently observed several brain regions that contribute ubiquitously to these abilities, including medial prefrontal cortex and aspects of lateral and medial parietal cortex. Interestingly, parallel work has suggested that this same network of regions subserves several seemingly distinct phenomena—notably, the abilities to remember the past, imagine the future and visualize spatial layouts—suggesting the existence of a common set of cognitive processes devoted to projecting oneself into worlds that differ mentally, temporally or physically from one's current experience. This use of self-projection to understand others' minds requires perceivers to solve three distinct cognitive challenges: (i) generating a simulated facsimile of one's own hypothetical mental states in a given situation, (ii) suppressing one's own current mental states, and (iii) deciding on the appropriateness of simulated states for understanding a particular other person. The present paper reviews recent psychology and neuroscience research aimed at understanding the underlying mechanisms that allow humans to solve each of these cognitive challenges to use self-projection to predict and understand the mental states of others.
A Mycorrhizal-Specific Ammonium Transporter from Lotus japonicus Acquires Nitrogen Released by Arbuscular Mycorrhizal Fungi
Authors: Guether Mike , Neuhäuser Benjamin , Balestrini Raffaella , Dynowski Marek , Ludewig Uwe , Bonfante Paola
Published: March 2009

In mycorrhizal associations, the fungal partner assists its plant host by providing nitrogen (N) in addition to phosphate. Arbuscular mycorrhizal (AM) fungi have access to inorganic or organic forms of N and translocate them via arginine from the extra- to the intraradical mycelium, where the N is transferred to the plant without any carbon skeleton. However, the molecular form in which N is transferred, as well as the involved mechanisms, is still under debate. NH4  + seems to be the preferential transferred molecule, but no plant ammonium transporter (AMT) has been identified so far. Here, we offer evidence of a plant AMT that is involved in N uptake during mycorrhiza symbiosis. The gene LjAMT2;2, which has been shown to be the highest up-regulated gene in a transcriptomic analysis of Lotus japonicus roots upon colonization with Gigaspora margarita, has been characterized as a high-affinity AMT belonging to the AMT2 subfamily. It is exclusively expressed in the mycorrhizal roots, but not in the nodules, and transcripts have preferentially been located in the arbusculated cells. Yeast (Saccharomyces cerevisiae) mutant complementation has confirmed its functionality and revealed its dependency on acidic pH. The transport experiments using Xenopus laevis oocytes indicated that, unlike other plant AMTs, LjAMT2;2 transports NH3 instead of NH4  +. Our results suggest that the transporter binds charged ammonium in the apoplastic interfacial compartment and releases the uncharged NH3 into the plant cytoplasm. The implications of such a finding are discussed in the context of AM functioning and plant phosphorus uptake.
In-Depth Proteome Analysis of Arabidopsis Leaf Peroxisomes Combined with in Vivo Subcellular Targeting Verification Indicates Novel Metabolic and Regulatory Functions of Peroxisomes
Authors: Reumann Sigrun , Quan Sheng , Aung Kyaw , Yang Pingfang , Manandhar-Shrestha Kalpana , Holbrook Danielle , Linka Nicole , Switzenberg Robert , Wilkerson Curtis G. , Weber Andreas P.M. , Olsen Laura J. , Hu Jianping
Published: March 2009

Peroxisomes are metabolically diverse organelles with essential roles in plant development. The major protein constituents of plant peroxisomes are well characterized, whereas only a few low-abundance and regulatory proteins have been reported to date. We performed an in-depth proteome analysis of Arabidopsis (Arabidopsis thaliana) leaf peroxisomes using one-dimensional gel electrophoresis followed by liquid chromatography and tandem mass spectrometry. We detected 65 established plant peroxisomal proteins, 30 proteins whose association with Arabidopsis peroxisomes had been previously demonstrated only by proteomic data, and 55 putative novel proteins of peroxisomes. We subsequently tested the subcellular targeting of yellow fluorescent protein fusions for selected proteins and confirmed the peroxisomal localization for 12 proteins containing predicted peroxisome targeting signals type 1 or 2 (PTS1/2), three proteins carrying PTS-related peptides, and four proteins that lack conventional targeting signals. We thereby established the tripeptides SLM> and SKV> (where > indicates the stop codon) as new PTS1s and the nonapeptide RVx5HF as a putative new PTS2. The 19 peroxisomal proteins conclusively identified from this study potentially carry out novel metabolic and regulatory functions of peroxisomes. Thus, this study represents an important step toward defining the complete plant peroxisomal proteome.
HER2 overexpression correlates with survival after curative resection of pancreatic cancer
Authors: Komoto Masahiro , Nakata Bunzo , Amano Ryosuke , Yamada Nobuya , Yashiro Masakazu , Ohira Masaichi , Wakasa Kenichi , Hirakawa Kosei
Published: March 2009

HER2 overexpression has been linked to clinical outcomes in several solid tumors, such as breast cancer. However, the correlation between HER2 overexpression and survival in pancreatic carcinoma remains unclear. The impact of HER2 overexpression on survival in pancreatic ductal cancer was examined. Immunohistochemical staining of 129 pancreatic cancers without hematogenous metastases or peritoneal dissemination treated by macroscopically curative resection were analyzed in association with survival data. To determine HER2 overexpression in this pancreatic cancer series, the polyclonal antibody included in HercepTest, which is used worldwide for clinical examination of HER2 overexpression in breast cancer, was used. Immunoreactivity was classified according to the scale presented in the HercepTest Scoring Guidelines. Twenty‐two cases (17.1%) had a score of 0, 28 cases (21.7%) had of a score of 1+, 41 cases (31.8%) had a score of 2+, and 38 cases (29.4%) had a score of 3+. Therefore, HER2 overexpression (score 2+ or 3+) was observed in 79 cases (61.2%). Patients with HER2 overexpression tumors had significantly shorter survival times than those with HER2 normal expression (score 0 or 1+) tumors (median survival time, 14.7 vs 20.7 months, respectively; P = 0.0078 on the log‐rank test). On multivariate survival analysis, HER2 overexpression remained an independent prognostic factor (hazard ratio, 1.806; P = 0.0258). A significant percentage of pancreatic cancers were demonstrated to have HER2 overexpression, and overexpression of this tyrosine kinase receptor proved to be an independent factor for a worse prognosis. These results should encourage further investigation of treatments using new molecular targeting agents against HER2 protein to improve the survival of pancreatic cancer patients. (Cancer Sci 2009; 100: 1243–1247)
Meta‐analysis: yield of diagnostic tests for coeliac disease in dyspepsia
Authors: FORD A. C. , CHING E. , MOAYYEDI P.
Published: March 2009

Background  The prevalence of coeliac disease (CD) may be increased in individuals with dyspepsia, but evidence is conflicting.

Aims  To conduct a systematic review and meta‐analysis of studies reporting prevalence of CD in dyspepsia.

Methods  MEDLINE, EMBASE, and CINAHL were searched up to February 2009. Case series and case‐control studies applying serological tests and/or distal duodenal biopsy for CD to unselected adults with dyspepsia were eligible. Prevalence of positive coeliac serology and biopsy‐proven CD were pooled for all studies and compared between cases and controls using an odds ratio (OR) and 95% confidence interval (CI).

Results  Fifteen studies were identified. Prevalence of positive coeliac serology was higher in cases with dyspepsia (7.9%) compared with controls (3.9%), but not significantly so (OR for positive endomysial antibodies or tissue transglutaminase 1.89; 95% CI 0.90–3.99). Prevalence of biopsy‐proven CD following positive serology was also higher (3.2% in cases vs. 1.3% in controls), but again this was not statistically significant (OR 2.85; 95% CI 0.60–13.38). Prevalence of biopsy‐proven CD was 1% in ten studies performing duodenal biopsy first‐line.

Conclusion  Prevalence of biopsy‐proven CD in subjects with dyspepsia was 1% and was higher than in controls, although this difference was not statistically significant.
Mild increases in serum hepcidin and interleukin‐6 concentrations impair iron incorporation in haemoglobin during an experimental human malaria infection
Authors: De Mast Quirijn , Van Dongen‐Lases Edmee C. , Swinkels Dorine W. , Nieman An‐Emmie , Roestenberg Meta , Druilhe Pierre , Arens Theo A. , Luty Adrian J. , Hermsen Cornelis C. , Sauerwein Robert W. , Van Der Ven Andre J.
Published: March 2009

The correct selection of individuals who will benefit from iron supplements in malaria‐endemic regions requires improved insight in the effects of malaria on host iron homeostasis and innovative biomarkers. We assessed sequential changes in serum hepcidin and in traditional biochemical iron status indicators during an experimental Plasmodium falciparum malaria infection with five adult volunteers. The haemoglobin content of reticulocytes (Ret‐He) and of mature red blood cells (RBC‐He) represented iron incorporation into haemoglobin. Low‐density parasitaemia and its treatment induced a mild increase in interleukin (IL)‐6 and serum hepcidin concentrations. Despite this only mild increase, a marked hypoferraemia with a strong increase in serum ferritin concentrations developed, which was associated with a sharp fall in Ret‐He, while RBC‐He remained unchanged. The ratio of soluble transferrin receptor (sTfR) to log ferritin concentrations decreased to an average nadir of 63% of the baseline value. We concluded that even mild increases in serum hepcidin and IL‐6 concentrations result in a disturbed host iron homeostasis. Serum hepcidin, Ret‐He and Delta‐He (Ret‐He minus RBC‐He) are promising biomarkers to select those individuals who will benefit from iron supplements in malaria endemic regions, while the sTfR/log ferritin ratio should be used with caution to assess iron status during malaria.
Long‐term follow‐up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis
Authors: Else Monica , Dearden Claire E. , Matutes Estella , Garcia‐Talavera Juan , Rohatiner Ama Z. S. , Johnson Steve A. N. , O’Connor Nigel T. J. , Haynes Andy , Osuji Nnenna , Forconi Francesco , Lauria Francesco , Catovsky Daniel
Published: March 2009

Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long‐term outlook. Median follow‐up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse‐free survival was 16 years. After relapse (n = 79) or non‐response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse‐free survival was 11 years. After third‐line therapy (n = 23), 50% achieved CR and median relapse‐free survival was 6·5 years. However, CRs were equally durable, whether after first, second or third‐line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 × 109/l before treatment had the longest relapse‐free survival (P < 0·0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL‐related causes. Patients achieving a CR can expect a normal lifespan.
Risk of non‐Hodgkin lymphoma in association with germline variation in complement genes
Authors: Cerhan James R. , Novak Anne J. , Fredericksen Zachary S. , Wang Alice H. , Liebow Mark , Call Timothy G. , Dogan Ahmet , Witzig Thomas E. , Ansell Stephen M. , Habermann Thomas M. , Kay Neil E. , Slager Susan L.
Published: March 2009

Germline mutations in complement genes have been associated with susceptibility to infections and autoimmune diseases, conditions that are associated with non‐Hodgkin lymphoma (NHL) risk. To test the hypothesis that common genetic variation in complement genes affect risk of NHL, we genotyped 167 single nucleotide polymorphisms (SNPs) from 31 genes in 441 NHL cases and 475 controls. Principal components (PC) and haplotype analyses were used for gene‐level tests of NHL risk, while individual SNPs were modelled as having a log‐additive effect. In gene level PC analyses, C2 (P = 0·023), C5 (P = 0·0032) and C9 (P = 0·020) were associated with NHL risk; haplotype analyses showed similar results, as well as a haplotype association for C7 (P = 0·046). When all four genes were considered simultaneously, only C5 and C9 remained significant (P < 0·05). In SNP level results from these genes, 10 SNPs had a P < 0·05. However, after correcting for multiple testing, only the C5 SNPs rs7026551 (q = 0·015; OR = 1·54, 95% CI 1·21–1·95) and rs2416810 (q = 0·015; OR = 1·57; 95% CI 1·22–2·01), and the C9 SNP rs187875 (q = 0·015; OR = 0·68; 95% 0·56–0·84) remained noteworthy. Associations were similar for the common NHL subtypes. In summary, we provide evidence for a role of genetic variation in complement genes, particularly C5 and C9, and NHL risk.
A phase 2 study of concurrent fludarabine and rituximab for the treatment of marginal zone lymphomas
Authors: Brown Jennifer R. , Friedberg Jonathan W. , Feng Yang , Scofield Sarah , Phillips Kimberly , Dal Cin Paola , Joyce Robin , Takvorian Ronald W. , Fisher David C. , Fisher Richard I. , Liesveld Jane , Marquis Diana , Neuberg Donna , Freedman Arnold S.
Published: March 2009

The marginal zone lymphomas (MZLs) are a recently defined group of related diseases that probably arise from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric mucosa‐associated lymphoid tissue (MALT) lymphoma has been largely limited to retrospective case series. This prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas enrolled 26 patients, 14 with nodal MZL, eight with MALT lymphomas and four with splenic MZL; 81% were receiving initial systemic therapy. Only 58% [95% confidence interval (CI) 37–77%] of patients completed the planned six cycles, due to significant haematological, infectious and allergic toxicity. Four late toxic deaths occurred due to infections [15% (95% CI 4·3–35%)], two related to delayed bone marrow aplasia and two related to myelodysplastic syndrome. Nonetheless, the overall response rate was 85% (95% CI 65–96%), with 54% complete responses. The progression‐free survival at 3·1 years of follow‐up is 79·5% (95% CI 63–96%). We conclude that, although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of MZLs, the significant haematological and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study MZLs as a separate entity.
Simultaneous targeting of MCL1 and ABCB1 as a novel strategy to overcome drug resistance in human leukaemia
Authors: Ji Min , Li Jie , Yu Haiqing , Ma Daoxin , Ye Jingjing , Sun Xiulian , Ji Chunyan
Published: March 2009

Drug resistance is a major obstacle to chemotherapy success in leukaemia. Although ABCB1 (MDR1) overexpression represents a critical mechanism of drug resistance, modulation of ABCB1 shows unsatisfactory clinical outcome. Recent studies showed that MCL1 was upregulated in numerous haematological and solid tumour malignancies. The present study found that patients with newly diagnosed or relapsed/refractory leukaemia expressed higher MCL1 levels than patients that were in complete remission. We demonstrated that overexpression of MCL1 decreased sensitivity of human leukaemia cell lines to cytotoxic drugs and inhibited drug‐induced apoptosis. Specific downregulation of MCL1 via RNA interference sensitized multidrug resistant leukaemia cells towards chemotherapy and induced apoptosis. Our study also demonstrated that MCL1 and ABCB1 mediated drug resistance through different mechanisms and the depletion of both MCL1 and ABCB1 showed an additive effect in reversing drug resistance and promoting drug‐induced apoptosis. Thus, this study documented an important role of MCL1 in drug resistance and apoptosis. Simultaneous targeting of MCL1 and ABCB1 could be a novel approach to overcome drug resistance in leukaemia.
Insulin sensitivity and body composition in children with classical and nonclassical congenital adrenal hyperplasia
Authors: Williams R. M. , Deeb A. , Ong K. K. , Bich W. , Murgatroyd P. R. , Hughes I. A. , Acerini C. L.
Published: March 2009

Background  Reduced insulin sensitivity and increased fat mass have been reported in children and adults with congenital adrenal hyperplasia (CAH). To understand the potential mechanisms underlying these differences, we assessed insulin sensitivity and body composition in children with classical or nonclassical (late‐presenting) CAH compared with normal controls.

Subjects and methods  Thirty‐seven children with CAH (26 classical and 11 nonclassical) median (range) age 9·4 year (0·5–15·8) were compared with 41 healthy control children age 11·0 year (3·2–17·1). All children had an overnight fasting blood sample and body composition assessed by DEXA. Pubertal children (14 CAH and 19 controls) also had an oral glucose tolerance test. Classical and nonclassical CAH groups were each compared with controls, adjusting for age, gender and pubertal status.

Results  Classical CAH children had more fat mass than controls (P = 0·03), while nonclassical CAH children had more lean mass (P = 0·006) and higher systolic blood pressure (P = 0·003) than control children. Among pubertal children, nonclassical CAH children had higher mean insulin (0–120 min; P = 0·04), stimulated insulin (0–30 min; P = 0·02), 120 min insulin (P = 0·004) and 120 min glucose levels (P = 0·03) than controls, but no difference in disposition index.

Discussion  Greater body fat in classical (early‐presenting) CAH children could reflect the effects of lifetime glucocorticoid therapy. In contrast, the greater lean mass and parameters of insulin resistance in nonclassical (late‐presenting) CAH children likely indicate the adverse metabolic effects of prolonged postnatal androgen excess.
Strong pH influence on N2O and CH4 fluxes from forested organic soils
Authors: Weslien P. , Kasimir Klemedtsson Å. , Börjesson G. , Klemedtsson L.
Published: March 2009

Greenhouse gas (GHG) emissions from farmed organic soils can have a major impact on national emission budgets. This investigation was conducted to evaluate whether afforestation of such soils could mitigate this problem. Over the period 1994–1997, emissions of methane (CH4) and nitrous oxide (N2O) were recorded from an organic soil site in Sweden, forested with silver birch (Betula pendula Roth), using static field chambers. The site was used for grazing prior to forestation. Soil pH and soil carbon content varied greatly across the site. The soil pH ranged from 3.6 to 5.9 and soil carbon from 34 to 42%.

The mean annual N2O emission was 19.4 (± 6.7) kg N2O‐N ha−1 and was strongly correlated with soil pH (r = −0.93, P < 0.01) and soil carbon content (r = 0.97, P < 0.001). The N2O emissions showed large spatial and temporal variability with greatest emissions during the summer periods. The site was a sink for CH4 (i.e. −0.8 (± 0.5) kg CH4 ha−1 year−1) and the flux correlated well with the C/N ratio (r = 0.93, P < 0.01), N2O emission (r = 0.92, P < 0.01), soil pH (r = −0.95, P < 0.01) and soil carbon (r = 0.97, P < 0.001). CH4 flux followed a seasonal pattern, with uptake dominating during the summer, and emission during winter.

This study indicates that, because of the large N2O emissions, afforestation may not mitigate the GHG emissions from fertile peat soils with acidic pH, although it can reduce the net GHG because of greater CO2 assimilation by the trees compared with agricultural crops.
Increasing ocean temperatures allow tropical fishes to survive overwinter in temperate waters
Authors: FIGUEIRA WILL F. , BOOTH DAVID J.
Published: March 2009

The southeast coast of Australia is a global hotspot for increasing ocean temperatures due to climate change. The temperate incursion of the East Australian Current (EAC) is increasing, affording increased connectivity with the Great Barrier Reef. The survival of tropically sourced juveniles over the winter is a significant stumbling block to poleward range shifts of marine organisms in this region. Here we examine the dependence of overwintering on winter severity and prewinter recruitment for eight species of juvenile coral reef fishes which are carried into temperate SE Australia (30–37 °S) by the EAC during the austral summer. The probability of persistence was most strongly influenced by average winter temperature and there was no effect of recruitment strength. Long‐term (138 years) data indicate that winter water temperatures throughout this region are increasing at a rate above the global average and predictions indicate a further warming of >2 °C by the end of the century. Rising ocean temperatures are resulting in a higher frequency of winter temperatures above survival thresholds. Current warming trajectories predict 100% of winters will be survivable by at least five of the study species as far south as Sydney (34 °S) by 2080. The implications for range expansions of these and other species of coral reef fish are discussed.
An evaluation of the PALS after treatment modelling intervention to reduce dental anxiety in child dental patients
Authors: HOWARD KAREN E. , FREEMAN RUTH
Published: March 2009

Aim.  The aim of this study was to assess the effectiveness of the passivity to activity through live symbolic (PALS) after treatment modelling intervention to reduce child dental anxiety.

Methods.  A convenience sample of consecutive 5‐ to 10‐year‐old dental patients were randomly assigned to intervention or control groups. Self‐reported child dental anxiety was assessed at the start of each visit. At the end of each visit, children in the intervention group were introduced to a glove puppet, which acted as the PALS model. The intervention group children re‐enacted the treatment they had just received on the puppet's teeth. At the end of each visit, the control children received motivational rewards only. The change in dental anxiety scores was examined by t‐tests and analysis of covariance.

Results.  The final analysis included 27 intervention children and 26 control children. For the intervention group, there were no statistically significant changes in dental anxiety over a course of treatment, between first and second preventive visits, between first and second invasive treatment visits, or between first attendance and subsequent recall attendance. For the control group, a statistically significant decrease in dental anxiety was observed between the first and second invasive dental treatment visits.

Conclusion.  The PALS after treatment modelling intervention was ineffective in reducing child dental anxiety.
Density‐dependence at multiple scales in experimental and natural plant populations
Authors: Gunton Richard M. , Kunin William E.
Published: March 2009

The survival and reproduction of individual plants may be related to the distribution of conspecific neighbours with which they interact.

We used 2 years’ data from a field experiment to relate the reproduction and survival of focal Silene latifolia plants to the numbers of conspecific plants and flowers within a range of distances (0.16–150 m) from the focal plants. Thus we consider spatial scale as a continuously‐varying component of population density.

Because the data come from a single continuous population, we fitted regression models in two stages in order to remove spatial autocorrelation induced by environmental factors before modelling density effects. As well as single‐scale models, we fitted multiple‐scale models to explore interaction kernels. We statistically standardized plant size in some analyses to isolate pollination effects.

Reproductive output per plant generally decreased with greater densities of plants and flowers; for example there was a negative effect of female flowers within a 70‐m radius in the second year. However, at low female densities there was a positive effect of male flowers at a scale of 13 m in the first year. Seed‐set per flower decreased with greater densities of flowers in the second year (at radii < 10 m). Seed predation was greater when more female flowers were present within 5–7 m. Plants’ survival probability increased with density within 0.28 m for all but the smallest plants.

We also collected data on the pattern and reproductive success of S. latifolia plants in a natural population nearby and applied similar methodology. Here the negative effects of female flower densities occurred at finer scales and gave way to positive effects above 2 m, contrasting with some patterns from the experiment.

Synthesis. In a sessile population interacting with mobile biota, the effects of density on individual fitness may vary with the way in which density is measured. This, together with the methodological challenges for analysing spatial data from continuous populations, should be considered when designing and interpreting studies of spatial density‐dependence. Taking these issues into account, we may begin to explain the spatial patterns of natural populations.
A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader–Willi syndrome via cognitive, environmental and physiological mechanisms
Authors: Woodcock K. A. , Oliver C. , Humphreys G. W.
Published: March 2009

Background  Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes.

Method  Taking Prader–Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics.

Results  The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage.

Conclusions  We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.
Monitoring adherence to beclomethasone in asthmatic children and adolescents through four different methods
Authors: Jentzsch N. S. , Camargos P. A. M. , Colosimo E. A. , Bousquet J.
Published: March 2009

Background:  Suboptimal adherence to inhaled steroids is a known problem in children and adolescents, even when medications are administered under parental supervision. This study aimed to verify the adherence rate to beclomethasone dipropionate (BDP) by four currently available methods.

Methods:  In this concurrent cohort study, 102 randomly selected asthmatic children and adolescents aged 3–14 years were followed for 12 months. Adherence rate was assessed every 2 months by self and/or parent report, pharmacy dispensing data, electronic device (Doser®; Meditrack Products, Hudson, MA, USA) monitor, and canister weight.

Results:  Mean adherence rates to BDP by self and/or parent report, pharmacy records, Doser, and canister weight were 97.9% (95% CI 88.0–98.6), 70.0% (95% CI 67.6–72.4), 51.5% (95% CI 48.3–54.6), and 46.3% (95% CI 44.1–48.4), respectively. Agreement analysis between (Doser) and canister weight revealed a weighted kappa equal to 0.76 (95% CI 0.65–0.87).

Conclusions:  Adherence was a dynamic event and rates decreased progressively for all methods over the 12‐month follow‐up. Canister weight and electronic monitoring measures were more accurate than self/parent reports and pharmacy records. Rates obtained by these two methods were very close and statistical analysis also showed a substantial agreement between them. As measurements by canister weight are less costly compared with currently available electronic devices, it should be considered as an alternative method to assess adherence in both clinical research and practice.
Thyroid hormones affect recovery from depression during antidepressant treatment
Authors: Pae Chi‐Un , Mandelli Laura , Han Changsu , Ham Byung‐Joo , Masand Prakash S. , Patkar Ashwin A. , Steffens David C. , De Ronchi Diana , Serretti Alessandro
Published: March 2009

Aims:  The aim of the present study was to evaluate whether thyroid hormonal changes during menopause may affect the development and the course of major depressive disorder.

Methods:  Thirty‐nine female patients (n = 17 in pre‐menopause; n = 22 in post‐menopause) with major depressive disorder based on Diagnostic Statistical Manual of Mental Disorders (4th edition) criteria and who were euthyroid and not on hormonal replacement therapy, participated in a prospective, 6‐week, open‐label naturalistic study. The Hamilton Depression Rating Scale‐17 item, the Montgomery‐Åsberg Depression Rating Scale, the Clinical Global Impression scale and the Cognitive Failure Questionnaire were administered at baseline, week 1, week 3, and week 6. Levels of thyroid stimulating hormone, total thyroxine and total triiodothyronine were collected at baseline visit.

Results:  In the whole sample, particularly in pre‐menopausal women, levels of thyroid stimulating hormone‐potential markers of subclinical hypothyroidism were correlated with those of less severe but more resistant depressive form. Conversely, total thyroxine levels were correlated with a more severe depression, but high levels of this hormone favored the response to antidepressants. Overall, a diagnosis of subclinical hypothyroidism was associated with a poor response to antidepressant treatment. Finally, total triiodothyronine levels were associated with better cognitive functioning, though they did not influence improvement occurring with recovery.

Conclusions:  Our study suggests that thyroid hormones may have an impact on severity and efficacy of antidepressant treatment. However, our result should be considered with caution and merely as a suggestion due to some methodological limitations. Hence further studies are required to better ascertain the role of thyroid hormones in depression after menopause.