bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired macrophage function following bacterial stimulation in chronic granulomatous disease
Authors: Rahman Farooq Z. , Hayee Bu’Hussain , Chee Ronnie , Segal Anthony W. , Smith Andrew M.
Published: April 2009

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is critical for phagocyte anti‐microbial activity and plays a major role in innate immunity. Defects in genes coding for components of the NADPH oxidase enzyme system are responsible for chronic granulomatous disease (CGD), a rare primary neutrophil immunodeficiency associated with recurrent, life‐threatening bacterial and fungal infections. Microbial killing and digestion within the neutrophil phagosomal compartment are defective in these patients. NADPH oxidase activity is also crucial for optimal macrophage and dendritic cell function and has recently been implicated in both cross‐presentation and T‐cell priming. We present evidence of impaired macrophage function in CGD, with attenuated pro‐inflammatory cytokine and increased interleukin‐10 secretion following bacterial stimulation. These results highlight additional abnormalities in macrophage function associated with CGD and the importance of NADPH oxidase activity in immunity.
Oral colonization by Lactobacillus reuteri ATCC 55730 after exposure to probiotics
Authors: ÇAGLAR ESBER , TOPCUOGLU NURSEN , ÇILDIR SULE KAVALOGLU , SANDALLI NUKET , KULEKCI GUVEN
Published: April 2009

Objective.  The aim of this study was to investigate whether Lactobacillus reuteri ATCC 55730 can be detected in the oral cavity after discontinuation of administration of a product prepared with this bacterium.

Materials and Methods.  The study consisted of three 2‐week periods: clearance period, intervention period, and post‐treatment period. Twenty‐five volunteers consumed a chewable tablet of L. reuteri ATCC 55730 (108 cfu/tablet) during a 14‐day trial period. Saliva samples were collected and cultured onto MRS agar after a clearance period of 2 weeks and then daily after a 2‐week intervention period for as long as L. reuteri was found. Lactobacillus reuteri colonies were analysed in saliva samples. The analysis was performed using selective media for L. reuteri followed by confirmation using the specific detection of reuterin produced by L. reuteri.

Results.  The number of L. reuteri carriers decreased gradually, and after 1 week only 8% of the subjects harboured the bacterium. After 5 weeks, L. reuteri was not detected in any of the subjects.

Conclusion.  Consuming L. reuteri for 2 weeks does not seem to be sufficient for permanent colonization of L. reuteri in the oral cavity.
Emergency department nurses’ understanding and experiences of implementing discharge planning
Authors: Han Chin‐Yen , Barnard Alan , Chapman Helen
Published: April 2009

Title.  Emergency department nurses’ understanding and experiences of implementing discharge planning.

Aim.  This paper is a report of a study conducted to describe emergency department nurses’ understanding and experiences of implementing discharge planning.

Background.  Discharge planning in the emergency department is an important issue because of increased healthcare costs and greater emphasis on continuity of care. When executed as a collaborative process involving a multi‐disciplinary team with the patient and family, discharge planning provides continuity of care for patients, less demand on hospitals, improvement in community services and in the services of other healthcare organizations.

Method.  The qualitative approach of phenomenography was used in this study. Thirty‐two emergency department nurses were recruited between July and September 2005. Semi‐structured interviews were conducted.

Findings.  From interviewees’ descriptions of implementing discharge planning, six categories were established: implementing discharge planning as ‘getting rid of my patients’, completing routines, being involved in patient education, professionally accountable practice, autonomous practice and demonstrating professional emergency department nursing care. The referential meaning of implementing discharge planning ‘in the outcome space’ was the professional commitment to emergency department provision of effective discharge services.

Conclusion.  The results of this research contribute to knowledge of emergency department nurses’ experience in the implementation of the discharge planning process. Key requirements for the provision of manageable discharge services both in Taiwan and worldwide highlighted by this study include adequate workloads, sufficient time, clear policies and standards of discharge planning and enhancement of professional commitment.
The Internet as a research site: establishment of a web‐based longitudinal study of the nursing and midwifery workforce in three countries
Authors: Huntington Annette , Gilmour Jean , Schluter Philip , Tuckett Anthony , Bogossian Fiona , Turner Catherine
Published: April 2009

Title.  The Internet as a research site: establishment of a web‐based longitudinal study of the nursing and midwifery workforce in three countries.

Aim.  The aim of this paper is to describe the development of a web‐based longitudinal research project, The Nurses and Midwives e‐cohort Study.

Background.  The Internet has only recently been used for health research. However, web‐based methodologies are increasingly discussed as significant and inevitable developments in research as Internet access and use rapidly increases worldwide.

Method.  In 2006, a longitudinal web‐based study of nurses and midwives workforce participation patterns, health and wellbeing, and lifestyle choices was established. Participating countries are Australia, New Zealand and the United Kingdom. Data collection is handled through a dedicated website using a range of standardized tools combined into one comprehensive questionnaire. Internet‐specific data collection and a range of recruitment and retention strategies have been developed for this study.

Discussion.  Internet‐based technology can support the maintenance of cohorts across multiple countries and jurisdictions to explore factors influencing workforce participation. However, barriers to widespread adoption of web‐based approaches include website development costs, the need for fast broadband connection for large data collection instruments, and varying degrees of Internet and computer literacy in the nursing and midwifery workforce.

Conclusion.  Many of the issues reported in this paper are transitional in nature at a time of rapid technological development. The development of on‐line methods and tools is a major and exciting development in the world of research. Research via the world‐wide web can support international collaborations across borders and cultures.
DNA‐based test: when and why to apply it to primary hyperparathyroidism clinical phenotypes
Authors: Falchetti A. , Marini F. , Giusti F. , Cavalli L. , Cavalli T. , Brandi M. L.
Published: April 2009

Several cancer‐related genes have been discovered and molecular test for the cancer genetic risk assessment has been widely increasing. Disorders such as Multiple Endocrine Neoplasia syndromes have received benefits from the identification of the responsible genes whose mutations account for the genetic susceptibility to develop endocrine tumours. Primary hyperparathyroidism (PHPT)is a clinical phenotype frequently associated to Multiple Endocrine Neoplasia syndromes, but it can also represent the unique endocrinopathy recurring as a familial cluster. In recent years, care options have been made available to patients and families with hereditary PHPT, and the process of systematically assessing the genetic risk has been becoming increasingly important. This review aims to help health providers not frequently dealing with genetic testing use and it will introduce some general concepts concerning genetic diagnosis issues. As an example the role and the practical usefulness of DNA‐based diagnosis in patients affected by different forms of congenital PHPT is described, with a close look on why, when and how genetic testing should be performed in these subjects and their relatives. Some practical recommendations and suggestions concerning on how to deal when a suspect or known case of familial PHPT has to be faced conclude this manuscript.
Medullary thyroid carcinoma and biomarkers: past, present and future
Authors: Van Veelen W. , De Groot J. W. B. , Acton D. S. , Hofstra R. M. W. , Höppener J. W. M. , Links T. P. , Lips C. J. M.
Published: April 2009

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long‐term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino‐embryonic antigen doubling‐time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.
Parafibromin – functional insights
Authors: Newey P. J. , Bowl M. R. , Thakker R. V.
Published: April 2009

Parafibromin is a predominantly nuclear protein with a tumour suppressor role in the development of hereditary and nonhereditary parathyroid carcinomas, and the hyperparathyroidism‐jaw tumour syndrome, which is associated with renal and uterine tumours. Parafibromin is a component of the highly conserved PAF1 complex, which regulates transcriptional events and histone modifications. The parafibromin/PAF1 complex regulates genes involved in cell growth and survival, and via these, parafibromin plays a pivotal role in embryonic development and survival of adults.
Multiple endocrine neoplasias: advances and challenges for the future
Authors: Alevizaki M. , Stratakis C. A.
Published: April 2009

Several important advances have been made over the last 2 years, since the last international workshop on multiple endocrine neoplasias (MENs) that was held in Marseilles, France (MEN2006). The series of articles that are included in this issue summarize the most important of these advances as they were presented in Delphi, Greece, during the 11th International Workshop on MENs, September 25–27, 2008 (MEN2008). This editorial summarizes some of these advances: the identification of the AIP, and the PDE11A and PDE8B genes by genome‐wide association (GWA) studies as predisposing genes for pituitary and adrenal tumours, respectively, the discovery of p27 mutations in a new form of MEN similar to MEN type 1 (MEN 1) that is now known as MEN 4, the molecular investigations of Carney triad (CT), a disorder that associates paragangliomas (PGLs), gastrointestinal stromal tumour (GISTs), and pulmonary chondromas (PCH) with pheochromocytomas and adrenocortical adenomas and other lesions, and the molecular elucidation of the association of GISTs with paragangliomas (Carney–Stratakis syndrome) that is now known to be because of SDHB, SDHC, and SDHD mutations. Molecular investigations in Carney complex (another MEN also described by Dr. Carney, who during the meeting, along with Dr. Charles E. (‘Gene’) Jackson was honoured for his life‐long and many contributions to the field) have also revealed the role of cyclic AMP signalling in tumorigenesis. As our knowledge of the molecular causes of MENs increases, the challenge is to translate these discoveries in better treatments for our patients. Indeed, new advances in the preventive diagnosis and molecular treatment of MEN 1 and MEN 2, respectively, continued unabated, and an update on this front was also presented at MEN2008 and is included in this issue.
SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma–paraganglioma syndromes
Authors: Pasini B. , Stratakis C. A.
Published: April 2009

A genetic predisposition for paragangliomas and adrenal or extra‐adrenal phaeochromocytomas was recognized years ago. Beside the well‐known syndromes associated with an increased risk of adrenal phaeochromocytoma, Von Hippel Lindau disease, multiple endocrine neoplasia type 2 and neurofibromatosis type 1, the study of inherited predisposition to head and neck paragangliomas led to the discovery of the novel ‘paraganglioma–phaeochromocytoma syndrome’ caused by germline mutations in three genes encoding subunits of the succinate dehydrogenase (SDH) enzyme (SDHB, SDHC and SDHD) thus opening an unexpected connection between mitochondrial tumour suppressor genes and neural crest‐derived cancers. Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma. The disease is characterized by autosomal dominant inheritance with a peculiar parent‐of‐origin effect for SDHD mutations. Life‐time tumour risk seems higher than 70% with variable clinical manifestantions depending on the mutated gene. In this review we summarize the most recent knowledge about the role of SDH deficiency in tumorigenesis, the spectrum and prevalence of SDH mutations derived from several series of cases, the related clinical manifestantions including rare phenotypes, such as the association of paragangliomas with gastrointestinal stromal tumours and kidney cancers, and the biological hypotheses attempting to explain genotype to phenotype correlation.
Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma
Authors: Santarpia L. , Ye L. , Gagel R. F.
Published: April 2009

Medullary thyroid carcinoma (MTC) is a rare calcitonin‐producing neuroendocrine tumour that originates from the parafollicular C‐cells of the thyroid gland. The RET proto‐oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30–50% of sporadic MTC cases, making this receptor an excellent target for small‐molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30–50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross‐talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET‐directed TKIs. Finally, there is evidence that immunological‐based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC‐specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates.
Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities
Authors: Machens A. , Lorenz K. , Dralle H.
Published: April 2009

The ground‐breaking discovery of genotype–phenotype relationships in hereditary medullary thyroid cancer has greatly facilitated early prophylactic thyroidectomy. Its timing depends not solely on a positive gene test but, more importantly, on the type of the REarranged during Transfection (RET) mutation and its underlying mode of RET receptor tyrosine kinase activation. In the past decade, the therapeutic corridor opened by molecular information has been defined down to a remarkable level of detail. Based on mutational risk profiles, preemptive thyroidectomy is recommended at 6 months of age for carriers of highest‐risk mutations, before the age of 5 years for carriers of high‐risk mutations, and before the age of 5 or 10 years for carriers of least‐high‐risk mutations. Additional lymph node dissection may not be needed in the absence of increased preoperative basal calcitonin levels. Better comprehension of RET function should enable the design of targeted therapies for RET carriers beyond surgical cure in whom the DNA‐based ‘window of opportunity’ has been missed.
Use of mouse models to understand the molecular basis of tissue‐specific tumorigenesis in the Carney complex
Authors: Kirschner L. S.
Published: April 2009

Carney complex (CNC) is an autosomal dominant, multiple endocrine neoplasia syndrome comprised of spotty skin pigmentation, myxomatosis, endocrine tumours and schwannomas. The majority of cases are due to inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of the 3′,5′‐cyclic adenosine monophosphate (cAMP)‐dependent protein kinase, PKA (protein kinase A). In order to understand the molecular basis for tumorigenesis associated with PRKAR1A mutations, we have developed conventional and conditional Prkar1a knockout (KO) mice as well as primary cell culture models corresponding to these genetic manipulations. At the biochemical level, removal of Prkar1a from cells causes enhanced PKA activity, the same effect which has been observed in tumours isolated from CNC patients. Mice heterozygous for Prkar1a mutations (the exact genetic model for CNC patients) are born at expected frequencies and are tumour prone, developing neoplasms in cAMP‐responsive cell types such as Schwann cells, osteoblasts and thyrocytes. In order to understand the basis of tissue‐specific tumour formation, we have created tissue‐specific KOs of the gene from three different tissues: the neural crest (Schwann cells), the pituitary gland and the heart. In the neural crest and the pituitary, ablation of Prkar1a leads to excess proliferation and tumorigenesis, whereas the same manipulation in developing cardiomyocytes leads to reduced proliferation and embryonic demise. The KO hearts also exhibit myxomatous changes suggesting a connection between PKA activation and myxomagenesis, although the nature of this relationship has not yet been determined. This work confirms the role of Prkar1a as a tissue‐specific tumour suppressor, and ongoing work is focused on identifying the key downstream signalling targets affected by dysregulation of PKA.
Coordination of cell proliferation and cell expansion mediated by ribosome‐related processes in the leaves of Arabidopsis thaliana
Authors: Fujikura Ushio , Horiguchi Gorou , Ponce María Rosa , Micol José Luis , Tsukaya Hirokazu
Published: April 2009

Co‐ordination of cell proliferation and cell expansion is a key regulatory process in leaf‐size determination, but its molecular details are unknown. In Arabidopsis thaliana, mutations in a positive regulator of cell proliferation often trigger excessive cell enlargement post‐mitotically in leaves. This phenomenon, called compensation syndrome, is seen in the mutant angustifolia3 (an3), which is defective in a transcription co‐activator. Such compensation, however, does not occur in response to a decrease in cell number in oligocellula (oli). oli2, oli5 and oli7 did not exhibit compensation and the reduction in cell number in these mutants was moderate. However, when an oli mutation was combined with a different oli mutation to create a double mutant, cell number was further reduced and compensation was induced. Similarly, weak suppression of AN3 expression reduced cell number moderately but did not induce compensation compared with an an3 null mutant. Furthermore, double mutants of either oli2, oli5 or oli7 and an3 showed markedly enhanced compensation. These results suggest that compensation is triggered when cell proliferation regulated by OLI2/OLI5/OLI7 and AN3 is compromised in a threshold‐dependent manner. OLI2 encodes a Nop2 homolog in Saccharomyces cerevisiae that is involved in ribosome biogenesis, whereas OLI5 and OLI7 encode ribosome proteins RPL5A and RPL5B, respectively. This suggests that a factor involved in the induction of compensation may be under the dual control of AN3 and a ribosome‐related process.
High frequency of single‐copy T‐DNA transformants produced by floral dip in CRE‐expressing Arabidopsis plants
Authors: De Paepe Annelies , De Buck Sylvie , Hoorelbeke Katleen , Nolf Jonah , Peck Ingrid , Depicker Anna
Published: April 2009

For genetic transformation of plants, floral dip with Agrobacterium often results in integration of multiple T‐DNA copies at a single locus and frequently in low and unstable transgene expression. To obtain efficient single‐copy T‐DNA transformants, two CRE/loxP recombinase‐based simplifying strategies for complex T‐DNA loci were compared. A T‐DNA vector with oppositely oriented loxP sites was transformed into CRE‐expressing and wild‐type control Arabidopsis thaliana plants. Of the primary CRE‐expressing transformants, 55% harboured a single copy of the introduced T‐DNA, but only 15% in the wild‐type plants. However, 73% of the single‐copy transformants in the CRE background showed continuous somatic inversion of the DNA segment between the two loxP sites. To avoid inversion of the loxP‐flanked T‐DNA segment, two T‐DNA vectors harbouring only one loxP site were investigated for their suitability for CRE/loxP recombinase‐mediated resolution upon floral‐dip transformation into CRE‐expressing plants. On average, 70% of the transformants in the CRE background were single‐copy transformants, whereas the single‐copy T‐DNA frequency was only 11% for both vectors in the wild‐type background. Both resolution strategies yielded mostly Cre transformants in which the 35S‐driven transgene expression was stable and uniform in the progeny and remarkably, also in Cre transformants with multiple T‐DNA copies. Therefore, a role is proposed for the CRE recombinase in preventing inverted T‐DNA repeat formation or modifying the locus chromatin structure, resulting in a reduced sensitivity for silencing.
AAP1 regulates import of amino acids into developing Arabidopsis embryos
Authors: Sanders Ann , Collier Ray , Trethewy Alexander , Gould Grant , Sieker Renate , Tegeder Mechthild
Published: April 2009

The embryo of Arabidopsis seeds is symplasmically isolated from the surrounding seed coat and endosperm, and uptake of nutrients from the seed apoplast is required for embryo growth and storage reserve accumulation. With the aim of understanding the importance of nitrogen (N) uptake into developing embryos, we analysed two mutants of AAP1 (At1g58360), an amino acid transporter that was localized to Arabidopsis embryos. In mature and desiccated aap1 seeds the total N and carbon content was reduced while the total free amino acid levels were strongly increased. Separately analysed embryos and seed coats/endosperm of mature seeds showed that the elevated amounts in amino acids were caused by an accumulation in the seed coat/endosperm, demonstrating that a decrease in uptake of amino acids by the aap1 embryo affects the N pool in the seed coat/endosperm. Also, the number of protein bodies was increased in the aap1 endosperm, suggesting that the accumulation of free amino acids triggered protein synthesis. Analysis of seed storage compounds revealed that the total fatty acid content was unchanged in aap1 seeds, but storage protein levels were decreased. Expression analysis of genes of seed N transport, metabolism and storage was in agreement with the biochemical data. In addition, seed weight, as well as total silique and seed number, was reduced in the mutants. Together, these results demonstrate that seed protein synthesis and seed weight is dependent on N availability and that AAP1‐mediated uptake of amino acids by the embryo is important for storage protein synthesis and seed yield.
VERNALIZATION INSENSITIVE 3 (VIN3) is required for the response of Arabidopsis thaliana seedlings exposed to low oxygen conditions
Authors: Bond Donna M. , Wilson Iain W. , Dennis Elizabeth S. , Pogson Barry J. , Jean Finnegan E.
Published: April 2009

VERNALIZATION INSENSITIVE 3 (VIN3), which is required for the vernalization‐mediated epigenetic repression of FLOWERING LOCUS C (FLC) in Arabidopsis thaliana, is quantitatively induced in response to low temperatures. We found that hypoxic conditions also induce VIN3 in a quantitative manner but high salt, high temperatures and osmotic stress do not. Inhibition of mitochondrial respiration did not induce VIN3 expression, consistent with the lack of VIN3 induction in response to other stresses that affect the rate of mitochondrial respiration. De novo protein synthesis is required for VIN3 induction during hypoxic conditions; this situation is not the case for VIN3 induction by low temperatures, indicating that different mechanisms act to induce VIN3 expression in response to cold and hypoxic conditions. Without VIN3 activity, fewer seedlings survived following a 72‐h period of hypoxic treatment, indicating that VIN3 is required for the survival of Arabidopsis thaliana in response to hypoxic stress. Complementation of the vin3 mutant with a VIN3 transgene restored the wild‐type response to low oxygen and confirmed the role of VIN3 in protecting both shoots and roots during low oxygen conditions. Loss of VIN3 protein did not affect the transcriptional regulation of genes known to be important in the response to low oxygen stress, which suggests that there is a novel mechanism to combat hypoxia that involves VIN3. This mechanism is likely to involve chromatin remodelling and may be similar to the role of VIN3 in the epigenetic repression of FLC during the vernalization response.
Predicting weed emergence in maize crops under two contrasting climatic conditions
Authors: DORADO J , SOUSA E , CALHA I M , GONZÁLEZ‐ANDÚJAR J L , FERNÁNDEZ‐QUINTANILLA C
Published: April 2009

Predictive empirical models of the timing of emergence were developed for ten major weed species in maize crops. Monitoring of seedling emergence was performed over two years in two maize fields located in Central Spain and Tagus Valley in Portugal. Thermal time was used as the independent variable for predicting cumulative emergence. Different non‐linear growth curves were fitted to the data sets of cumulative percent emergence for the different species, sites and years using genetic algorithms. Based on their emergence patterns, weed species were arranged into three groups. Species with early‐season emergence (Abutilon theophrasti, Xanthium strumarium, Datura stramonium, Datura ferox, Sorghum halepense, Digitaria sanguinalis and Echinochloa crus‐galli) reached 70% emergence with less than 700 growing day degrees (GDD). Species with whole‐season emergence (Cyperus rotundus and Solanum nigrum) started early their emergence processes but the emergence continued throughout the maize life‐cycle; they required up to 1300 GDD to reach 70% emergence. The only species with late‐season emergence was Sonchus oleraceus; it required more than 1300 GDD to reach 70% emergence. The results obtained in our experiments have shown a good synchrony between the predictions obtained in different years in the same site. However, no single model was able to predict the timing of emergence in two sites with different environmental conditions, challenging the hypothesis that a single general model, based on temperature only, can be used to predict weed emergence in different geographical locations.
Penetrance and clinical consequences of a gross SDHB deletion in a large family
Authors: Solis DC , Burnichon N , Timmers HJLM , Raygada MJ , Kozupa A , Merino MJ , Makey D , Adams KT , Venisse A , Gimenez‐Roqueplo A‐P , Pacak K
Published: April 2009

Mutations in the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) are inherited in an autosomal dominant manner and are associated with hereditary paraganglioma (PGL) and pheochromocytoma. The phenotype of patients with SDHB point mutations has been previously described. However, the phenotype and penetrance of gross SDHB deletions have not been well characterized as they are rarely described. The objective was to describe the phenotype and estimate the penetrance of an exon 1 large SDHB deletion in one kindred. A retrospective and prospective study of 41 relatives across five generations was carried out. The main outcome measures were genetic testing, clinical presentations, plasma catecholamines and their O‐methylated metabolites. Of the 41 mutation carriers identified, 11 were diagnosed with PGL, 12 were found to be healthy carriers after evaluation, and 18 were reportedly healthy based on family history accounts. The penetrance of PGL related to the exon 1 large SDHB deletion in this family was estimated to be 35% by age 40. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion was observed, including low penetrance, diverse primary PGL tumor locations, and malignant potential.
The association between HLA‐A, ‐B alleles and major histocompatibility complex class I polymorphic Alu insertions in four populations in China
Authors: Yao Y. , Shi L. , Shi L. , Lin K. , Yu L. , Sun H. , Huang X. , Tao Y. , Yi W. , Liu S. , Chu J.
Published: April 2009

The study of the association between polymorphic Alu insertions [human leukocyte antigen (HLA)‐Alu] at five loci and HLA class I alleles at two loci allows for better identification of the origins and evolution of HLA class I region haplotypes in different populations. In the present study, we determined the frequencies of five HLA‐Alus and their associations with HLA‐A and ‐B alleles in Han, Wa, Maonan, and Jinuo populations. Our results showed a strong association between AluHG insertion and HLA‐A*02 in all populations studied; however, the associations between AluHJ insertion and HLA‐A*1101 and HLA‐A*2402 and AluHF insertion and HLA‐A*2601 were only observed in Han. The AluMICB insertion showed a strong association with HLA‐B*5502 in Han, Maonan, and Jinuo. HLA‐A*0101, HLA‐A*0201, HLA‐A*0203, HLA‐A*1101, HLA‐A*2402, HLA‐A*2601, and HLA‐A*3101 alleles were associated with one or more of the three different Alu elements within the alpha block as independent haplotypes, and HLA‐A*0101, HLA‐A*0201, HLA‐A*0203, HLA‐A*1101, and HLA‐A*2402 alleles were associated with at least two different Alu insertions as a haplotype within the alpha block. We conclude that the HLA class I region haplotypes of the four populations were derived from different progenitor haplotypes, and relatively high rates of recombination between individuals with HLA‐A alleles and different HLA‐Alus occurred in this region.
Role of polymorphisms in the TNFRSF13B (TACI) gene in Spanish patients with immunoglobulin A deficiency
Authors: López‐Mejías R. , Del Pozo N. , Fernández‐Arquero M. , Ferreira A. , García‐Rodríguez M. C. , De La Concha E. G. , Fontán G. , Urcelay E. , Martínez A. , Núñez C.
Published: April 2009

Mutations in the TNFRSF13B (TACI) gene have been associated with common variable immunodeficiency, and a role in immunoglobulin A deficiency (IgAD) has also been suggested. We aimed at studying the role of several polymorphisms along this gene in IgAD susceptibility. Three TNFRSF13B mutations (C104R, A181E and R202H) and eight additional single nucleotide polymorphisms in the gene were genotyped in 338 Spanish IgAD patients and 553 ethnically matched healthy controls and tested for association. Data from parents of 114 IgAD patients were also collected and used for additional analysis. No statistically significant differences were observed after comparing patients and controls for any single nucleotide polymorphism analysed. Therefore, our work seems to discard a role of TNFRSF13B mutations in IgAD, concordantly with the most recent published studies.
Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor
Authors: Shigeta Takanobu , Kasahara Mureo , Kimura Takuya , Fukuda Akinari , Sasaki Kazunari , Arai Katsuhiro , Nakagawa Atsuko , Nakagawa Satoshi , Kobayashi Keiko , Soneda Shun , Kitagawa Hiroaki
Published: April 2009

Shigeta T, Kasahara M, Kimura T, Fukuda A, Sasaki K, Arai K, Nakagawa A, Nakagawa S, Kobayashi K, Soneda S, Kitagawa H. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr Transplantation 2010: 14:E86–E88. © 2009 John Wiley Sons & A/S.

Abstract:  NICCD is an autosomal recessive genetic disorder, characterized by cholestasis, coagulopathy, hypoglycemia, fatty liver and multiple amino acidemia. NICCD develops in the neonatal/infantile period and has been reported as a “naturally curable” disease within one yr of life. Recently, we experienced an infantile NICCD who developed progressive liver failure, and required subsequent LT using a heterozygote living donor at eight months of age. Diagnosis of NICCD was established before transplantation, and donor evaluation included mutation in the SLC25A13 gene for exclusion of individuals with citrin deficiency citrullinemia. LDLT, from blood type identical mother using a left lateral segment graft, was performed without serious complication. Plasma amino acid concentration was normalized rapidly, and the patient was discharged 30 days after transplant. During one yr follow up, the recipient has been doing well without additional medication for NICCD. NICCD should be considered in the differential diagnosis as a cause of neonatal/infantile cholestatic disease. LT using a heterozygote living donor is an effective alternative in countries where a deceased donor is not available.
Clinical manifestations and survival of hepatocellular carcinoma patients with peritoneal metastasis
Authors: Lin Chien‐Chu , Liang Hsiao‐Ping , Lee Hsuan‐Shu , Huang Guan‐Tarn , Yang Pei‐Ming , Ho Ming‐Chih , Lee Po‐Huang , Tsang Yuk‐Ming , Chen Ding‐Shinn , Sheu Jin‐Chuan , Chen Chien‐Hung
Published: April 2009

Background and Aim:  Peritoneal metastasis is an uncommon manifestation of hepatocellular carcinoma (HCC). The aim of the present paper was to investigate the characteristics and survival of HCC patients with peritoneal metastases.

Methods:  From January 1985 to December 2004, we retrospectively reviewed the records of 53 Taiwanese HCC patients with peritoneal metastases.

Results:  Peritoneal metastases were detected at the time of HCC diagnosis (synchronously) in 10 patients and after the initial therapy for the primary tumors (metachronously) in 43 patients. The mean time for development of the metachronous peritoneal metastases was similar whether the primary cancer was treated with surgery (24 months) or transarterial chemoembolization (22.2 months). The single patient whose primary cancer was treated with supportive care alone developed peritoneal metastasis only 7.5 months after detection of the primary cancer. Surgical resection of the peritoneal metastases was possible in two‐thirds of the 43 metachronous patients. The median survival for those who received surgery for these metastases was 12.5 months vs. 2.1 months for those without surgery (P = 0.0013). However, there was no difference in survival if patients were stratified to Child‐Pugh grade.

Conclusions:  Peritoneal metastases of HCC are rare and can occur synchronously or metachronously. Though increased long‐term survival was found in patients who had surgical removal of peritoneal metastases, the main determinant of better survival is Child‐Pugh grade.
Vertebrate range sizes indicate that mountains may be ‘higher’ in the tropics
Authors: McCain Christy M.
Published: April 2009

In 1967, Daniel Janzen proposed the influential, but largely untested hypothesis, that tropical mountain passes are physiologically higher than temperate mountains. I test his key prediction, the one upon which all the others rely: namely, that elevational range sizes of organisms get larger on mountains at increasing latitudes. My analyses use 170 montane gradients spanning 36.5° S to 48.2° N latitude compiled from over 80 years of research and 16 500 species of rodents, bats, birds, lizards, snakes, salamanders, and frogs. In support of Janzen’s prediction, I find that elevational range size increases with increasing latitude for all vertebrate groups except rodents. I document additional lines of evidence for temperature variability as a plausible mechanism for trends in vertebrate range size, including strong effects of thermoregulation and daily temperature variability, and a weak effect of precipitation.
Socioeconomic factors related to attendance at a Type 2 diabetes screening programme
Authors: Dalsgaard E‐M. , Lauritzen T. , Christiansen T. , Mai K. S. , Borch‐Johnsen K. , Sandbæk A.
Published: April 2009

Aims  The prevalence of diabetes is increasing, and screening of high‐risk populations is recommended. A low attendance rate has been observed in many Type 2 diabetes screening programmes, so that an analysis of factors related to attendance is therefore relevant. This paper analyses the association between socioeconomic factors and attendance for Type 2 diabetes screening.

Methods  Persons aged 40–69 years (n = 4603) were invited to participate in a stepwise diabetes screening programme performed in general practitioners’ offices in the county of Aarhus, Denmark in 2001. The study was population‐based and cross‐sectional with follow‐up. The association between screening attendance in the high‐risk population and socioeconomic factors was analysed by odds ratio.

Results  Forty‐four percent of the estimated high‐risk population attended the screening programme. In those with known risk for Type 2 diabetes, attenders were more likely to be older, to be unemployed and to live in the countryside than non‐attenders. The risk for Type 2 diabetes was unknown for 21% of the study population; this group was younger and less likely to be cohabitant, skilled, or employed and to have middle or high income than the study population with known risk score for diabetes.

Conclusions  A low attendance rate was found in this screening programme for Type 2 diabetes. No substantial socioeconomic difference was found between attenders and non‐attenders in the high‐risk population. Further research is needed to uncover barriers to screening of Type 2 diabetes in socioeconomically deprived persons.
Alkalinization of urine samples preserves albumin concentrations during prolonged frozen storage in patients with diabetes mellitus
Authors: Lambers Heerspink H. J. , Nauta F. L. , Van Der Zee C. P. , Brinkman J. W. , Gansevoort R. T. , De Zeeuw D. , Bakker S. J. L.
Published: April 2009

Background  In epidemiological studies in patients with diabetes, urine samples are often stored frozen prior to assessment of urinary albumin concentration (UAC). However, prolonged frozen storage may result in a falsely low UAC. In the current study, we investigated whether adjustment of urinary pH to alkaline values prior to frozen storage can prevent this problem.

Methods  Urine samples were collected in 90 patients from our diabetes outpatient clinic and divided into two portions. One portion was first adjusted to pH > 8.0 with 0.1 m sodium hydroxide, the other was left unprocessed. Both portions were divided into aliquots. UAC was assessed in fresh samples and after 7 days, 1, 6 and 12 months of storage at −20 and −80°C.

Results  Until 1 month of storage there were no significant changes in UAC. After longer storage, UAC fell significantly in pH unadjusted samples stored at −20°C, with a −7.6% (27.8) and −13.6% (31.7) change after 6 and 12 months storage, respectively. No significant change in UAC occurred in pH adjusted samples stored at −20°C or when samples were stored at −80°C, both with and without pH adjustment. Variation in UAC assessed after 12 months of storage was larger for samples stored at −20°C without adjustment of pH than for the samples stored with pH adjustment or stored at −80°C.

Conclusions  Urine alkalinization to pH > 8.0 prevents the decline in UAC associated with 12 months of frozen storage at −20°C and results in lower variation between samples after storage.
Fungal foot infection, cellulitis and diabetes: a review
Authors: Bristow I. R. , Spruce M. C.
Published: April 2009

Aims  To review the current evidence for the presence of fungal foot infection (tinea pedis and toenail onychomycosis) as a risk factor for the development of cellulitis within the lower limb, particularly for those individuals with diabetes.

Methods  A structured review of medline, embase and cinahl databases was undertaken to identify publications investigating fungal foot infection as a risk factor for the development of cellulitis.

Results  Sixteen studies were identified. Eight studies adopted a case–control methodology, with the remainder being cross‐sectional surveys. The majority of studies established the presence of tinea infection by clinical rather than established microbiological methods. Although the majority of papers suggested a link, only two case–control studies employed microbiological diagnosis to demonstrate that fungal foot infection was a risk for the development of lower limb cellulitis, particularly when infection was located between the toes. There were insufficient data to suggest that fungal foot infection posed an increased risk to patients with diabetes.

Conclusion  There is some evidence to suggest that fungal infection of the foot is a factor in the development of lower limb cellulitis, but further robust research is needed to confirm these findings and quantify the risk that fungi pose, particularly to the diabetic foot. Meanwhile, improved surveillance and treatment of tinea infections on the foot by healthcare professionals should be encouraged to reduce potential complications.
Randomized controlled trial to assess the impact of continuous glucose monitoring on HbA1c in insulin‐treated diabetes (MITRE Study)
Authors: Cooke D. , Hurel S. J. , Casbard A. , Steed L. , Walker S. , Meredith S. , Nunn A. J. , Manca A. , Sculpher M. , Barnard M. , Kerr D. , Weaver J. U. , Ahlquist J. , Newman S. P.
Published: April 2009

Aims  To determine whether continuous glucose information provided through use of either the GlucoWatch G2 Biographer or the MiniMed continuous glucose monitoring system (CGMS) results in improved glycated haemoglobin (HbA1c) for insulin‐treated adults with diabetes mellitus, relative to an attention control and standard care group.

Methods  Four hundred and four adults taking at least two daily insulin injections and with two consecutive HbA1c values ≥ 7.5% were recruited to this randomized controlled trial (RCT). All were trained at baseline to use the same monitor for traditional capillary glucose testing throughout the 18‐month study. The CGMS group were asked to wear the device three times during the first 3 months of the trial and on another three occasions thereafter. The GlucoWatch group wore the device a minimum of four times per month and a maximum of four times per week during the first 3 months and as desired for the remainder of the trial. Trained diabetes research nurses used downloaded data to guide therapy adjustments. Proportional reduction in HbA1c from baseline to 18 months was the primary outcome measure.

Results  Neither an intention‐to‐treat nor per‐protocol analysis showed improvement in HbA1c in the device groups compared with standard care. For the intention‐to‐treat analysis, when the standard care group was compared with each of the other groups, this equated to differences in mean relative HbA1c reduction (95% confidence interval) from baseline to 18 months of 3.5% (−1.3 to 8.3; GlucoWatch), 0.7% (−4.1 to 5.5; CGMS), and −0.1% (−4.6 to 4.3; attention control).

Conclusions  The additional information provided by these devices did not result in improvements in HbA1c in this population.
Effects of rosiglitazone and pioglitazone on lipoprotein metabolism in patients with Type 2 diabetes and normal lipids
Authors: Brackenridge A. L. , Jackson N. , Jefferson W. , Stolinski M. , Shojaee‐Moradie F. , Hovorka R , Umpleby A. M. , Russell‐Jones D.
Published: April 2009

Aims  Previous studies have suggested that plasma lipids are affected differently by the peroxisome proliferators‐activated receptor (PPAR)‐γ agonists pioglitazone and rosiglitazone. The aim of this study was to perform a quantitative lipoprotein turnover study to determine the effects of PPAR‐γ agonists on lipoprotein metabolism.

Methods  Twenty‐four subjects with Type 2 diabetes treated with diet and/or metformin were randomized in a double‐blind study to receive 30 mg pioglitazone, 8 mg rosiglitazone or placebo once daily for 3 months. Before and after treatment, absolute secretion rate (ASR) and fractional catabolic rate (FCR) of very low‐density lipoprotein (VLDL), intermediate‐density lipoprotein (IDL) and low‐density lipoprotein (LDL) apolipoprotein B100 were measured with a 10‐h infusion of 1‐13C leucine.

Results  There was a significant decrease in glycated haemoglobin (HbA1c) and non‐esterified fatty acids with pioglitazone (P = 0.01; P = 0.02) and rosiglitazone (P = 0.04; P = 0.003), respectively, but no change in plasma triglyceride or high‐density lipoprotein (HDL) cholesterol. Following rosiglitazone, there was a significant reduction in VLDL apolipoprotein B100 (apoB) ASR (P = 0.01) compared with baseline, a decrease in VLDL triglyceride/apoB (P = 0.01), an increase in LDL2 cholesterol (P = 0.02) and a decrease in LDL3 cholesterol (P = 0.02). There was a decrease in VLDL triglyceride/apoB (P = 0.04) in the pioglitazone group. There was no significant difference in change in VLDL ASR or FCR among the three groups.

Conclusions  In patients with Type 2 diabetes and normal lipids, treatment with rosiglitazone or pioglitazone had no significant effect on lipoprotein metabolism compared with placebo.
Reforming pensions: Principles, analytical errors and policy directions
Authors: Barr Nicholas , Diamond Peter
Published: April 2009

This article, sets out a series of principles for pension design rooted in economic theory: pension systems have multiple objectives, analysis should consider the pension system as a whole, analysis should be framed in a second‐best context, different systems share risks differently, and systems have different effects by generation and by gender. That discussion is reinforced by identification of a series of widespread analytical errors — errors that appear in World Bank work, but by no means only in World Bank work: tunnel vision, improper use of first‐best analysis, improper use of steady‐state analysis, incomplete analysis of implicit pension debt, incomplete analysis of the impact of funding (including excessive focus on financial flows, failure to consider how funding is generated, and improper focus on the type of asset in trust funds), and ignoring distributional effects. The second part of the article considers implications for policy: there is no single best pension design, earlier retirement does little or nothing to reduce unemployment, unsustainable pension promises need to be addressed directly, a move from pay‐as‐you‐go towards funding in a mandatory system may or may not be welfare improving, and implementation matters — policy design that exceeds a country's capacity to implement it is bad policy design. We illustrate the ranges of designs of pension systems that fit the fiscal and institutional capacity constraints typical at different levels of economic development. The potential gains from simplicity imply that a country capable of implementing an administratively demanding plan does not necessarily gain from doing so. New Zealand has a simple pension system through choice, not constraint.