bluuebunny/crossref_metadata_2025 huggingface dataset:
The zebrafish
kohtalo/trap230
gene is required for the development of the brain, neural crest, and pronephric kidney
Authors: Hong Sung-Kook , Haldin Caroline E. , Lawson Nathan D. , Weinstein Brant M. , Dawid Igor B. , Hukriede Neil A.
Published: December 2005

Mutation of the gene encoding the Mediator component thyroid hormone receptor-associated protein (TRAP)230/MED12 affects the development of multiple systems in zebrafish embryogenesis. We isolated two ethylnitrosourea-induced alleles in the gene encoding this protein and named the locus
kohtalo
(
kto
) after the homologous locus in
Drosophila
. Homozygous
kto
mutant zebrafish embryos show defects in brain, neural crest, and kidney development and die at ≈6 days postfertilization. In the affected tissues, differentiation is initiated and many cell type-specific genes are expressed, but there is a failure of morphogenesis and failure to complete differentiation. These results suggest that critical targets of TRAP230 function may include proteins important for cell mobility, cell sorting, and tissue assembly.
In vivo
targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles
Authors: Kwon Young Jik , James Edward , Shastri Nilabh , Fréchet Jean M. J.
Published: December 2005

Activating the immune system to trigger a specific response is a major challenge in vaccine development. In particular, activating sufficient cytotoxic T lymphocyte-mediated cellular immunity, which is crucial for the treatment of many diseases including cancer and AIDS, has proven to be especially challenging. In this study, antigens were encapsulated in acid-degradable polymeric particle carriers to cascade cytotoxic T lymphocyte activation. To target dendritic cells, the most potent antigen-presenting cells, the particle carriers, were further conjugated with monoclonal antibodies. A series of
ex vivo
and
in vivo
studies have shown increased receptor-mediated uptake of antibody-conjugated particles by dendritic cells as well as migration of particle-carrying dendritic cells to lymph nodes and stimulation of naïve T cells leading to enhanced cellular immune response as confirmed by specific cell lysis and IFN-γ secretion.
Let's Put Garbage-Can Regressions and Garbage-Can Probits Where They Belong
Authors: Achen Christopher H.
Published: December 2005

Many social scientists believe that dumping long lists of explanatory variables into linear regression, probit, logit, and other statistical equations will successfully “control” for the effects of auxiliary factors. Encouraged by convenient software and ever more powerful computing, researchers also believe that this conventional approach gives the true explanatory variables the best chance to emerge. The present paper argues that these beliefs are false, and that without intensive data analysis, linear regression models are likely to be inaccurate. Instead, a quite different and less mechanical research methodology is needed, one that integrates contemporary powerful statistical methods with deep substantive knowledge and classic data—analytic techniques of creative engagement with the data.
Rule of Three, Let It Be? When More Really Is Better
Authors: Oneal John R. , Russett Bruce
Published: December 2005

Jim Ray and others in this issue question customary procedures for the quantitative analysis of theoretically complex questions in the social sciences. In this article we address Ray's use of research on the Kantian peace to illustrate his points. We discuss his five guidelines for research, indicating how we agree and disagree, and take up five substantive issues he has raised about our research. With new analyses to supplement our previous work, we show that none of his reservations is well founded. We discuss the costs as well as the benefits of rigid insistence on reducing the number of independent variables in a regression equation.
‘WHEN ARE THE CHILDREN GOING TO LEAVE HOME!’: FAMILY CULTURE AND DELAYED TRANSITIONS IN SPAIN
Authors: Holdsworth Clare
Published: December 2005

This paper distinguishes the characteristics of recent trends towards older ages of leaving home in Spain. Based on analysis of in-depth interviews with young people and parents from Bilbao in the Basque Country, I explore how familism and family solidarity play a key role in the current trend towards delayed family formation, focusing on the postponement of leaving home. This analysis illustrates the various leaving home strategies that young Basque people adopt, and how these are negotiated with parents and other family members. The analysis of the interview data also captures the ways in which young people negotiate with and recreate family culture, both while living in and leaving the parental home. The different strategies adopted by young people are classified by a typology based on the extent to which young people recognise and conform to a prescribed cultural model of behaviour, namely leaving home to get married and (preferably) buy a property.
Regulation of Sar1 NH2 terminus by GTP binding and hydrolysis promotes membrane deformation to control COPII vesicle fission
Authors: Bielli Anna , Haney Charles J. , Gabreski Gavin , Watkins Simon C. , Bannykh Sergei I. , Aridor Meir
Published: December 2005

The mechanisms by which the coat complex II (COPII) coat mediates membrane deformation and vesicle fission are unknown. Sar1 is a structural component of the membrane-binding inner layer of COPII (Bi, X., R.A. Corpina, and J. Goldberg. 2002. Nature. 419:271–277). Using model liposomes we found that Sar1 uses GTP-regulated exposure of its NH2-terminal tail, an amphipathic peptide domain, to bind, deform, constrict, and destabilize membranes. Although Sar1 activation leads to constriction of endoplasmic reticulum (ER) membranes, progression to effective vesicle fission requires a functional Sar1 NH2 terminus and guanosine triphosphate (GTP) hydrolysis. Inhibition of Sar1 GTP hydrolysis, which stabilizes Sar1 membrane binding, resulted in the formation of coated COPII vesicles that fail to detach from the ER. Thus Sar1-mediated GTP binding and hydrolysis regulates the NH2-terminal tail to perturb membrane packing, promote membrane deformation, and control vesicle fission.
Effects of Multiple Metal Binding Sites on Calcium and Magnesium-dependent Activation of BK Channels
Authors: Hu Lei , Yang Huanghe , Shi Jingyi , Cui Jianmin
Published: December 2005

BK channels are activated by physiological concentrations of intracellular Ca2+ and Mg2+ in a variety of cells. Previous studies have identified two sites important for high-affinity Ca2+ sensing between [Ca2+]i of 0.1–100 μM and a site important for Mg2+ sensing between [Mg2+]i of 0.1–10 mM. BK channels can be also activated by Ca2+ and Mg2+ at concentrations >10 mM so that the steady-state conductance and voltage (G-V) relation continuously shifts to more negative voltage ranges when [Mg2+]i increases from 0.1–100 mM. We demonstrate that a novel site is responsible for metal sensing at concentrations ≥10 mM, and all four sites affect channel activation independently. As a result, the contributions of these sites to channel activation are complex, depending on the combination of Ca2+ and Mg2+ concentrations. Here we examined the effects of each of these sites on Ca2+ and Mg2+-dependent activation and the data are consistent with the suggestion that these sites are responsible for metal binding. We provide an allosteric model for quantitative estimation of the contributions that each of these putative binding sites makes to channel activation at any [Ca2+]i and [Mg2+]i.
Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates
Authors: Khan Hameed , Smit Arian , Boissinot Stéphane
Published: December 2005

We investigated the evolution of the families of LINE-1 (L1) retrotransposons that have amplified in the human lineage since the origin of primates. We identified two phases in the evolution of L1. From ∼70 million years ago (Mya) until ∼40 Mya, three distinct L1 lineages were simultaneously active in the genome of ancestral primates. In contrast, during the last 40 million years (Myr), i.e., during the evolution of anthropoid primates, a single lineage of families has evolved and amplified. We found that novel (i.e., unrelated) regulatory regions (5′UTR) have been frequently recruited during the evolution of L1, whereas the two open-reading frames (ORF1 and ORF2) have remained relatively conserved. We found that L1 families coexisted and formed independently evolving L1 lineages only when they had different 5′UTRs. We propose that L1 families with different 5′UTR can coexist because they don't rely on the same host-encoded factors for their transcription and therefore do not compete with each other. The most prolific L1 families (families L1PA8 to L1PA3) amplified between 40 and 12 Mya. This period of high activity corresponds to an episode of adaptive evolution in a segment of ORF1. The correlation between the high activity of L1 families and adaptive evolution could result from the coevolution of L1 and a host-encoded repressor of L1 activity.
Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS)
Authors: Crawford Gregory E. , Holt Ingeborg E. , Whittle James , Webb Bryn D. , Tai Denise , Davis Sean , Margulies Elliott H. , Chen YiDong , Bernat John A. , Ginsburg David , Zhou Daixing , Luo Shujun , Vasicek Thomas J. , Daly Mark J. , Wolfsberg Tyra G. , Collins Francis S.
Published: December 2005

A major goal in genomics is to understand how genes are regulated in different tissues, stages of development, diseases, and species. Mapping DNase I hypersensitive (HS) sites within nuclear chromatin is a powerful and well-established method of identifying many different types of regulatory elements, but in the past it has been limited to analysis of single loci. We have recently described a protocol to generate a genome-wide library of DNase HS sites. Here, we report high-throughput analysis, using massively parallel signature sequencing (MPSS), of 230,000 tags from a DNase library generated from quiescent human CD4+ T cells. Of the tags that uniquely map to the genome, we identified 14,190 clusters of sequences that group within close proximity to each other. By using a real-time PCR strategy, we determined that the majority of these clusters represent valid DNase HS sites. Approximately 80% of these DNase HS sites uniquely map within one or more annotated regions of the genome believed to contain regulatory elements, including regions 2 kb upstream of genes, CpG islands, and highly conserved sequences. Most DNase HS sites identified in CD4+ T cells are also HS in CD8+ T cells, B cells, hepatocytes, human umbilical vein endothelial cells (HUVECs), and HeLa cells. However, ∼10% of the DNase HS sites are lymphocyte specific, indicating that this procedure can identify gene regulatory elements that control cell type specificity. This strategy, which can be applied to any cell line or tissue, will enable a better understanding of how chromatin structure dictates cell function and fate.
Variation in crossing-over rates across chromosome 4 of Arabidopsis thaliana reveals the presence of meiotic recombination “hot spots”
Authors: Drouaud Jan , Camilleri Christine , Bourguignon Pierre-Yves , Canaguier Aurélie , Bérard Aurélie , Vezon Daniel , Giancola Sandra , Brunel Dominique , Colot Vincent , Prum Bernard , Quesneville Hadi , Mézard Christine
Published: December 2005

Crossover (CO) is a key process for the accurate segregation of homologous chromosomes during the first meiotic division. In most eukaryotes, meiotic recombination is not homogeneous along the chromosomes, suggesting a tight control of the location of recombination events. We genotyped 71 single nucleotide polymorphisms (SNPs) covering the entire chromosome 4 of Arabidopsis thaliana on 702 F2 plants, representing 1404 meioses and allowing the detection of 1171 COs, to study CO localization in a higher plant. The genetic recombination rates varied along the chromosome from 0 cM/Mb near the centromere to 20 cM/Mb on the short arm next to the NOR region, with a chromosome average of 4.6 cM/Mb. Principal component analysis showed that CO rates negatively correlate with the G+C content (P =3×10-4), in contrast to that reported in other eukaryotes. COs also significantly correlate with the density of single repeats and the CpG ratio, but not with genes, pseudogenes, transposable elements, or dispersed repeats. Chromosome 4 has, on average, 1.6 COs per meiosis, and these COs are subjected to interference. A detailed analysis of several regions having high CO rates revealed “hot spots” of meiotic recombination contained in small fragments of a few kilobases. Both the intensity and the density of these hot spots explain the variation of CO rates along the chromosome.
Effect of a laxative with and without tegaserod in adolescents with constipation predominant irritable bowel syndrome
Authors: KHOSHOO V. , ARMSTEAD C. , LANDRY L.
Published: December 2005

Aim

To determine the effect of a laxative alone and in combination with tegaserod in alleviating pain and improving stool frequency in adolescents with constipation predominant irritable bowel syndrome.

Patients

Forty‐eight postpubertal adolescents of both sexes with constipation predominant irritable bowel syndrome, as defined by Rome II criteria, were randomly allocated to Group A (n = 27) for treatment with a laxative (polyethylene glycol 3350 oral solution) only or Group B (n = 21) for combination therapy with the laxative and tegaserod. Symptoms of abdominal pain (scale 0–10) and frequency of bowel movements were recorded daily in the pre‐treatment phase and the post‐treatment phase after a 7‐day ‘washout’ period. Patients served as their own controls.

Results

Treatment with the laxative alone (Group A) resulted in significant increase in frequency of bowel movements (P < 0.05), but not significant improvement in pain (P > 0.05). Treatment with the combination of the laxative and tegaserod (Group B) led to significant increase in the frequency of bowel movements and also significant reduction in pain (P < 0.05).

Conclusions

The laxative alone improved stooling but not pain in adolescents with constipation predominant irritable bowel syndrome. Addition of tegaserod resulted in alleviation of pain as well.
Blood oxidative stress markers are unreliable markers of hepatic steatosis
Authors: BONNEFONT‐ROUSSELOT D. , RATZIU V. , GIRAL P. , CHARLOTTE F. , BEUCLER I. , POYNARD T. ,   FOR THE LIDO STUDY GROUP
Published: December 2005

Background

Non‐alcoholic fatty liver disease (NAFLD) and viral hepatitis are associated with hepatic oxidative stress, which is partially dependent on the amount of hepatic fat.

Aim

To determine whether the circulating lipid and oxidative stress parameters could be non‐invasive markers of hepatic steatosis.

Methods

Sixty‐four patients with NAFLD or viral hepatitis were tested for lipid peroxidation products and antioxidant defence systems, lipid parameters and liver function tests.

Results

Hepatic steatosis was correlated with lipids, γ‐glutamyltranspeptidase, thiobarbituric acid‐reactive substances, superoxide dismutase and superoxide dismutase/erythrocyte glutathione peroxidase ratio. γ‐Glutamyltranspeptidase, triglycerides and low‐density lipoprotein cholesterol were significantly higher in the presence of steatosis. No difference in blood oxidative stress markers was observed according to the presence or absence of steatosis except for the superoxide dismutase/erythrocyte glutathione peroxidase ratio. Total cholesterol, triglycerides and low‐density lipoprotein cholesterol were significantly higher in the NAFLD group (n = 17, 60% mean steatosis grade) than in the viral hepatitis group (n = 20, 13% mean steatosis grade). Only superoxide dismutase was lower and vitamin E higher in NAFLD than in viral hepatitis patients.

Conclusions

Standard blood oxidative stress markers do not predict the extent of hepatic steatosis as they probably do not accurately reflect intrahepatic oxidative stress. Serum lipid levels were best correlated with hepatic steatosis.
Statins and the risk of acute pancreatitis: a population‐based case–control study
Authors: THISTED H. , JACOBSEN J. , MUNK E. M. , NØRGAARD B. , FRIIS S. , McLAUGHLIN J. K. , SØRENSEN H. T. , JOHNSEN S. P.
Published: December 2005

Background

Case reports have suggested that statins may cause acute pancreatitis.

Aim

To examine if statins are associated with risk of acute pancreatitis.

Methods

We identified 2576 first‐time admitted cases of acute pancreatitis from hospital discharge registers in three Danish counties, and 25 817 age‐ and gender‐matched controls from the general population. Prescriptions for statins prior to admission with acute pancreatitis or index date among controls were retrieved from prescription databases. We used conditional logistic regression analysis to estimate odds ratios for acute pancreatitis among ever (ever before), current (0–90 days before), new (first prescription in 0–90 days before) and former (>90 days, but not 0–90 days before) users of statins.

Results

Adjusted odds ratios for acute pancreatitis among ever, current, new and former users of statins were 1.44 (95% confidence interval: 1.115–1.80), 1.26 (95% confidence interval: 0.96–1.64), 1.01 (95% confidence interval: 0.43–2.37) and 2.02 (95% confidence interval: 1.37–2.97), respectively. There was an indication of an inverse association between the number of filled prescriptions and risk of acute pancreatitis.

Conclusions

Our findings speak against a strong causative effect of statins on the risk of acute pancreatitis, and may even indicate a mild protective effect.
High accuracy and cost‐effectiveness of a biopsy‐avoiding endoscopic approach in diagnosing coeliac disease
Authors: CAMMAROTA G. , CESARO P. , MARTINO A. , ZUCCALÀ G. , CIANCI R. , NISTA E. , LAROCCA L. M. , VECCHIO F. M. , GASBARRINI A. , GASBARRINI G.
Published: December 2005

Background

The ‘immersion’ technique during upper endoscopy allows the visualization of duodenal villi and the detection of total villous atrophy.

Aim

To evaluate the accuracy of the immersion technique in detecting total villous atrophy in suspected coeliac patients. The accuracy in diagnosing coeliac disease and the potential cost‐sparing of a biopsy‐avoiding approach, based on selection of individuals with coeliac disease‐related antibodies and on endoscopic detection of absence of villi, were also analysed.

Methods

The immersion technique was performed in 79 patients with positive antibodies and in 105 controls. Duodenal villi were evaluated as present or absent. As reference, results were compared with histology. Diagnostic approaches, including endoscopy with or without biopsy, were designed to investigate patients with coeliac disease‐related antibodies and total villous atrophy. A cost‐minimization analysis was performed.

Results

All patients with positive antibodies had coeliac disease. The sensitivity, specificity, positive and negative predictive values of endoscopy to detect total villous atrophy was always 100%. The sensitivity, specificity, positive and negative predictive values of biopsy‐avoiding or biopsy‐including strategies in diagnosing coeliac disease when villi were absent was always 100%. The biopsy‐avoiding strategy was cost‐sparing.

Conclusions

Upper endoscopy is highly accurate in detecting total villous atrophy coeliac patients. A biopsy‐avoiding approach is both accurate and cost‐sparing to diagnose coeliac disease in subjects with marked duodenal villous atrophy.
Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome
Authors: HELMY A.
Published: December 2005

Hepatic sinusoidal obstruction syndrome is frequently linked to high‐dose chemotherapy/total‐body irradiation in recipients of haematopoietic stem cell transplantation, long‐term use of azathioprine after organ transplantation and other chemotherapeutic agents. The incidence of hepatic sinusoidal obstruction syndrome varies from 0% to 70%, and is decreasing.

Disease risk is higher in patients with malignancies, hepatitis C virus infection, those who present late, when norethisterone is used to prevent menstruation, and when broad‐spectrum antibiotics and antifungals are used during and after the conditioning therapy. Hepatic sinusoidal obstruction syndrome presents with tender hepatomegaly, hyperbilirubinaemia and ascites, and diagnosis is mainly clinical (Seattle and Baltimore Criteria). Imaging excludes biliary obstruction and malignancy, but cannot establish accurate diagnosis. Hepatic sinusoidal obstruction syndrome may be prevented by avoiding the highest risk regimens, using non‐myeloablative regimens, and reducing total‐body irradiation dose.

Treatment is largely symptomatic and supportive, because 70–80% of patients recover spontaneously. Tissue plasminogen activator plus heparin improves outcome in <30% of cases. Defibrotide, a polydeoxyribonucleotide, is showing encouraging results. Transjugular intrahepatic porto‐systemic shunt relieves ascites, but does not improve outcome.

Liver transplantation may be an option in the absence of malignancy. Prognosis is variable and depends on disease severity, aetiology and associated conditions. Death is most commonly caused by renal or cardiopulmonary failure.
Systematic review: coxibs, non‐steroidal anti‐inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high‐risk patients?
Authors: NIELSEN O. H. , AINSWORTH M. , CSILLAG C. , RASK‐MADSEN J.
Published: December 2005

Selective cyclooxygenase‐2 inhibitors have been marketed as alternatives of conventional, non‐steroidal anti‐inflammatory drugs with the purpose of reducing/eliminating the risk of ulcer complications. Unexpectedly, randomized‐controlled trials revealed that long‐term use of coxibs, such as rofecoxib, significantly increased the risk of myocardial infarction and stroke, while the use of valdecoxib was associated with potentially life‐threatening skin reactions.

Subsequently, rofecoxib and valdecoxib were withdrawn from the market. Although more strict precautions for other coxibs, such as celecoxib, etoricoxib, lumiracoxib and parecoxib, may be accepted/recommended by regulatory agencies, a critical review of published data suggests that their use may not be justified – even in high‐risk patients – taking benefits, costs and risks into consideration. Clinicians should, therefore, never prescribe coxibs to patients with cardiovascular risk factors, and should only reluctantly prescribe coxibs to patients with a history of ulcer disease or dyspepsia to overcome persistent pain due to, e.g. rheumatoid arthritis or osteoarthritis.

Instead, they should consider using conventional non‐steroidal anti‐inflammatory drugs in combination with a proton pump inhibitor or a prostaglandin analogue, especially for patients with increased cardiovascular risks, i.e. established ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease, or alternatively acetaminophen. An evidence‐based algorithm for treatment of a chronic arthritis patient with one or more gastrointestinal risk factors is presented.
Increase of bioavailable testosterone is associated with gain in bone mineral density after cure of primary hyperparathyroidism in postmenopausal women
Authors: Almqvist Erik G. , Becker Charlotte , Bondeson Anne‐Greth , Bondeson Lennart , Svensson Johan
Published: December 2005

Objective  The recovery of bone mineral density (BMD) after surgical cure of primary hyperparathyroidism (PHPT) seems to be multifactorial and not just dependent on declining PTH. The aim of the present study was to evaluate the role of sex steroids in this context.

Design and patients  Thirty‐six postmenopausal women with PHPT were examined before and 1 year after curative parathyroidectomy. Their mean age at inclusion in the study was 71·7 ± 1·1 years (range 54–83). BMD was measured in hip and lumbar spine using dual energy X‐ray absorptiometry. No patient received any replacement therapy with sex hormones or treatment with corticosteroids, oestrogen receptor modulators or bisphosphonates.

Measurements  Serum concentrations of oestradiol, testosterone, androstenedione, dehydroepiandrosterone sulphate, SHBG, PTH and calcium.

Results  Postoperative increase of free (bioavailable) testosterone was positively correlated to the change of BMD in the hip (P < 0·01), whereas the change of PTH in serum correlated to the change of BMD in the lumbar spine (P < 0·05). Multiple regression analysis showed that bioavailable testosterone was the most important determinant of change in BMD in both spine and hip (femoral neck: P < 0·05; Ward's triangle: P < 0·001; trochanter: P < 0·01; lumbar spine: P < 0·05). The increase of bioavailable testosterone after curative parathyroidectomy was related to declining SHBG.

Conclusions  An increase of bioavailable testosterone following surgical cure of PHPT is related to improvement of hip and lumbar spine BMD in postmenopausal women. This previously unknown hormonal interaction may also be important to other aspects of hyperparathyroidism.
Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women
Authors: Kim Duk Jae , Khang Young Ho , Koh Jung‐Min , Shong Young Kee , Kim Ghi Su
Published: December 2005

Objective  Hyperthyroidism is accompanied by low bone mass. Because the reference range of TSH levels is defined statistically, some individuals with low normal TSH levels may have mild hyperthyroidism and reduced bone mass. We therefore determined whether serum TSH levels correlate with bone mineral density (BMD).

Design  A cross‐sectional hospital‐based survey.

Participants  Nine hundred and fifty‐nine healthy postmenopausal women.

Measurements  We measured BMD at the lumbar spine and femoral neck using dual energy X‐ray absorptiometry, and serum TSH concentrations using immunoluminometry.

Results  BMD at the lumbar spine and femoral neck increased with TSH level (P for trend < 0·001 at both sites). Even after adjustment for age, years since menopause and body mass index, subjects with low normal TSH levels (0·5–1·1 mU/l) had significantly lower BMDs at the lumbar spine (0·863 ± 0·009 g/cm2vs 0·900 ± 0·009 g/cm2, P = 0·004) and femoral neck (0·660 ± 0·006 g/cm2vs 0·683 ± 0·006 g/cm2, P = 0·006) than those with high normal TSH levels (2·8–5·0 mU/l), as well as a 2·2‐fold increased risk of osteoporosis (95% confidence interval: 1·2–4·0).

Conclusion  These results suggest that low normal TSH levels may not be physiological for postmenopausal women and, during treatment of hypothyroidism, may not be adequate for avoiding osteoporosis.
Does the prevalence of gsp mutations in GH‐secreting pituitary adenomas differ geographically or racially? Prevalence of gsp mutations in Japanese patients revisited
Authors: Yasufuku‐Takano Junko , Takano Koji , Morita Koji , Takakura Kintomo , Teramoto Akira , Fujita Toshiro
Published: December 2005

Objective   The prevalence of gsp mutations in GH‐secreting pituitary adenomas was thought to differ geographically or racially, given its exceptionally lower incidence among Japanese patients (4·4–9·3%) compared to other regions (30–50%). However, this notion is now being challenged after a recent paper reported a 53·3% incidence among Japanese with acromegaly. We have since re‐evaluated the prevalence of gsp mutations on a larger scale.

Patients   One hundred Japanese acromegaly patients with surgically confirmed GH‐secreting pituitary adenomas were enrolled.

Methods   mRNAs from primary cultured adenomas were used for reverse transcriptase–polymerase chain reaction and direct sequencing of the Gsα subunit. Patient data were reviewed from medical charts.

Results   There were 53 gsp mutations (53%), consisting of 42 Arg201Cys, one Arg201His, one Arg201Ser, 8 Gln227Leu, and one Gln227Arg mutation. Age at operation, sex ratio, basal serum GH and IGF‐I levels were no different with or without the mutations. In contrast, patients responded differently to most dynamic tests with statistical significance: serum GH levels in gsp‐positive patients had blunted response to GHRH, were well suppressed by bromocriptine, and had higher rates of paradoxical response to TRH. Notably, paradoxical response to LHRH was observed exclusively in gsp‐negative patients. Octreotide suppressed GH levels strongly regardless of gsp status. These clinical characteristics are similar to those of Caucasian patients.

Conclusion   We conclude that the prevalence of gsp mutations in Japanese acromegaly patients is comparable to those of other reports from various regions. Therefore, Japanese patients do not stand as an example for geographical or racial difference in the prevalence of gsp mutations in GH‐secreting pituitary adenomas.
Enhanced and prolonged cross‐presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles
Authors: Shen Hong , Ackerman Anne L. , Cody Virginia , Giodini Alessandra , Hinson Ella R. , Cresswell Peter , Edelson Richard L. , Saltzman W. Mark , Hanlon Douglas J.
Published: December 2005

CD8+ T‐cell responses are critical in the immunological control of tumours and infectious diseases. To prime CD8+ T cells against these cell‐associated antigens, exogenous antigens must be cross‐presented by professional antigen‐presenting cells (APCs). While cross‐presentation of soluble antigens by dendritic cells is detectable in vivo, the efficiency is low, limiting the clinical utility of protein‐based vaccinations. To enhance the efficiency of presentation, we generated nanoparticles from a biodegradable polymer, poly(d,l‐lactide‐co‐glycolide) (PLGA), to deliver antigen into the major histocompatibility complex (MHC) class I antigen presentation pathway. In primary mouse bone marrow‐derived dendritic cells (BMDCs), the MHC class I presentation of PLGA‐encapsulated ovalbumin (OVA) stimulated T cell interleukin‐2 secretion at 1000‐fold lower concentration than soluble antigen and 10‐fold lower than antigen‐coated latex beads. The microparticles also served as an intracellular antigen reservoir, leading to sustained MHC class I presentation of OVA for 72 hr, decreasing by only 20% after 96 hr, a time at which the presentation of soluble and latex bead‐associated antigens was undetectable. Cytosol extraction demonstrated that antigen delivery via PLGA particles increased the amount of protein that escaped from endosomes into the cytoplasm, thereby increasing the access of exogenous antigen to the classic MHC class I loading pathway. These data indicate that the unique properties of PLGA particle‐mediated antigen delivery dramatically enhance and sustain exogenous antigen presentation by MHC class I, potentially facilitating the clinical use of these particles in vaccination.
DNA repair, a novel antibacterial target: Holliday junction‐trapping peptides induce DNA damage and chromosome segregation defects
Authors: Gunderson Carl W. , Segall Anca M.
Published: December 2005

Holliday junction intermediates arise in several central pathways of DNA repair, replication fork restart, and site‐specific recombination catalysed by tyrosine recombinases. Previously identified hexapeptide inhibitors of phage lambda integrase‐mediated recombination block the resolution of Holliday junction intermediates in vitro and thereby inhibit recombination, but have no DNA cleavage activity themselves. The most potent peptides are specific for the branched DNA structure itself, as opposed to the integrase complex. Based on this activity, the peptides inhibit several unrelated Holliday junction‐processing enzymes in vitro, including the RecG helicase and RuvABC junction resolvase complex. We have found that some of these hexapeptides are potent bactericidal antimicrobials, effective against both Gm+ and Gm– bacteria. Using epifluorescence microscopy and flow cytometry, we have characterized extensively the physiology of bacterial cells treated with these peptides. The hexapeptides cause DNA segregation abnormalities, filamentation and DNA damage. Damage caused by the peptides induces the SOS response, and is synergistic with damage caused by UV and mitomycin C. Our results are consistent with the model that the hexapeptides affect DNA targets that arise during recombination‐dependent repair. We propose that the peptides trap intermediates in the repair of collapsed replication forks, preventing repair and resulting in bacterial death. Inhibition of DNA repair constitutes a novel target of antibiotic therapy. The peptides affect targets that arise in multiple pathways, and as expected, are quite resistant to the development of spontaneous antibiotic resistance.
Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study)
Authors: Kurzawski G , Suchy J , Lener M , Kłujszo‐Grabowska E , Kładny J , Safranow K , Jakubowska K , Jakubowska A , Huzarski T , Byrski T , Dębniak T , Cybulski C , Gronwald J , Oszurek O , Oszutowska D , Kowalska E , Góźdź S , Niepsuj S , Słomski R , Pławski A , Łącka‐Wojciechowska A , Rozmiarek A , Fiszer‐Maliszewska Ł , Bębenek M , Sorokin D , Sąsiadek MM , Stembalska A , Grzebieniak Z , Kilar E , Stawicka M , Godlewski D , Richter P , Brożek I , Wysocka B , Limon J , Jawień A , Banaszkiewicz Z , Janiszewska H , Kowalczyk J , Czudowska D , Scott RJ , Lubiński J
Published: December 2005

Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non‐polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA‐testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty‐six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty‐four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation‐dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.
Maternal urinary steroid profiles in prenatal diagnosis of Smith–Lemli–Opitz syndrome: first patient series comparing biochemical and molecular studies
Authors: Jezela‐Stanek A , Małunowicz EM , Ciara E , Popowska E , Goryluk‐Kozakiewicz B , Spodar K , Czerwiecka M , Jezuita J , Nowaczyk MJM , Krajewska‐Walasek M
Published: December 2005

Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive disorder caused by reduced activity of 7‐dehydrocholesterol (7DHC) reductase, resulting in a decreased level of cholesterol and increased concentrations of 7DHC and 8DHC in body fluids and tissues. Ten pregnancies at 25% risk of SLOS underwent prenatal testing. Diagnostic studies included DHCR7 mutation analysis in chorionic villus samples, amniotic fluid sterol analysis and serial measurements of oestriol (E3), pregnanetriol (PT), 7‐dehydropregnanetriol (7DHPT) and 8‐dehydroesteriol (8DHE3) concentrations in maternal urine samples obtained between 9 and 20 weeks of gestation. All tests were diagnostic and revealed nine unaffected foetuses (two normal homozygotes and seven DHCR7 heterozygotes) and one affected foetus. In the affected pregnancy, 7DHC and 8DHC in amniotic fluid were 9.87 and 3.7 µg/ml, respectively [reference range (RR) 0.0026 ± 0.0015 µg/ml and not detectable, respectively] and maternal urinary steroid analyses showed increased ratios of 7DHPT/PT and 8DHE3/E3 of 0.74 and 1.7, respectively (RR 0–0.0147 and 0–0.019). In the heterozygous foetuses, 7DHPT/PT and 8DHE3/E3 ratios did not exceed those found in 48 normal controls. This is the first series of prenatal diagnostic testing for SLOS where non‐invasive biochemical testing was performed in tandem with invasive diagnostic testing. We conclude that steroid measurements in maternal urine are a reliable means of prenatal diagnosis for SLOS.
Adams–Oliver syndrome: clinical description of a four‐generation family and exclusion of five candidate genes
Authors: Verdyck P , Blaumeiser B , Holder‐Espinasse M , Van Hul W , Wuyts W
Published: December 2005

We present a Belgian Adams–Oliver syndrome (AOS) family with 10 affected individuals over four generations, of which six were available for this study. Clinical symptoms observed in these patients were very variable as previously reported in other families and included large areas of alopecia on the vertex of the skull and serious limb reduction defects with agenesis of all toes of one foot. To identify the disease‐causing gene, we sequenced the MSX1, CART1, P63 (P73L), RUNX2, and HOXD13 genes in this family and nine previously reported families, but no disease‐causing mutations were found. Further investigation is ongoing in these families in order to identify the genetic cause of AOS.
Relative migration rates and local adaptation in a mosquito-protozoan interaction
Authors: Ganz H. H. , Washburn J. O.
Published: December 2005

Theory predicts that the direction of local adaptation depends on the relative migration rates of hosts and parasites. Here we measured relative migration rates and tested for local adaptation in the interaction between a tree hole mosquito (Ochlerotatus sierrensis) and a protozoan parasite (Lambornella clarki). We found strong support for the hypothesis that the host migrates more than its parasite. Hosts colonized artificial tree holes in the field at a much higher rate than the parasite. Field releases of the parasite demonstrated that it colonizes and persists in natural tree holes where it was previously absent, suggesting that parasite distribution is limited by its migratory ability. Although the host migrates more than its parasite, we found no evidence for local adaptation by hosts and some evidence for local adaptation by parasites. Other life history traits of the host and parasite may also influence patterns in local adaptation, particularly parasite virulence and host dormancy.
Analysis of the importance of genotypic variation, metabolic rate, morphology, sex and development time on immune function in the cricket, Gryllus firmus
Authors: Rantala M. J. , Roff D. A.
Published: December 2005

Immune defence is hypothesized to be a trait that bears significant fitness costs as well as benefits in that mounting a defence depreciates the value of other life-history traits. Thus the cost of mounting an immune response could affect the evolution of both the immune system and correlated life history traits. In this study we examined, by means of a diallel cross of four inbred lines, the genetic basis of two measures of immune function, metabolic rate and several traits in the sand cricket, Gryllus firmus. We specifically addressed the following questions: (1) is immune function determined primarily by genetic constitution or correlations with phenotypic traits that could reduce the effectiveness of the immune response; (2) do the two measures of immune function covary; (3) What are the contributions of additive, nonadditive and maternal effects to the immune function? As estimates of immune function, we used lytic activity and encapsulation rate. We found that inbred crickets were smaller than individuals from the crossed lines and took longer to develop. However, inbred lines did not differ from the crossed lines in immune function nor metabolic rates, suggesting that increased homozygosity has little or no effect on these traits in G. firmus. We found that both immune parameters showed significant genetic variation but no consistent relationships with the other phenotypic traits (metabolic rate, head width, body mass, development time and activity). There was significant additive genetic variation only in encapsulation rate, but, with the exception of the activity measure, significant nonadditive and reciprocal variances were found in all traits. Metabolic rate of crickets was heritable, but there was neither phenotypic nor genetic association between metabolic rate and the two parameters of immune function. Further, there was no correlation between these two measures. Females showed a higher encapsulation response than males, but there was no sex differences in lytic activity. Our study indicates that genetic variation in immune parameters can be a very significant contributor to phenotypic variation in immune function.
Mineralogical and geochemical investigation of sediment in the Snake River arm of the Dillon Reservoir, Summit County, Colorado, USA
Authors: Conaway Christopher H. , Pride D. E. , Faure Gunter , Tettenhorst R. T.
Published: December 2005

Mineralogical and chemical analyses of sediment in the Snake River arm of the Dillon Reservoir provided insight into the transport and fate of trace metals in this system, which provides potable water to the city of Denver in Colorado. The sediments contain metal hydroxide precipitates and sorbed trace metals that formed upstream in the Snake River and in Deer Creek, Peru Creek and other tributaries. Iron and trace metal concentrations in the sediments reach a maximum about halfway down the 3.3 km arm, with their distribution probably controlled by physical processes acting on the settling of precipitates entering the arm from the mouth of the Snake River. The concentration of molybdenum is at background concentration near the mouth of the Snake River, increasing towards the centre of the reservoir, where values are 10 times greater, owing to contamination from the Ten Mile Creek and Blue River arms of the reservoir. The results of a sediment‐leaching experiment demonstrated that the relative ease of extraction with a decreasing pH value in the sediments is zinc > cobalt > copper > nickel > lead. Although most of the trace metals are low in concentration, or are strongly sorbed in the sediments, the relatively high concentration of zinc and its relatively high mobility make it a metal of potential concern in the reservoir.
Pesticide residues in Volta Lake, Ghana
Authors: Ntow William Joseph
Published: December 2005

The Volta River basin comprises ≈ 70% of mainland Ghana, being inhabited by a majority of the country's population. The purpose of this study was to analyse water and sediment samples at six locations in Volta Lake for residues of persistent organochlorine pesticides. Residues were extracted by use of two types of extractions, including a standardized solid phase extraction procedure for water samples and a Soxhlet extraction procedure for sediment samples. All samples were analysed by gas chromatography. Lindane and endosulfan were identified in concentrations ≤ 0.008 p.p.b. and 0.036 p.p.b., respectively, in water, and ≤ 2.3 p.p.b. and 0.36 p.p.b., respectively, in sediments. Dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene were also found in sediment samples (in concentrations ≤ 9.0 p.p.b. and 52.3 p.p.b., respectively). No significant contamination was noted in the lake. The distribution of pesticide residues in water and neighbouring sediment are briefly discussed. Different bioconcentration factors obtained in this study allowed the confirmation of the complex processes already reported in the literature regarding the partitioning of chemicals between sediment and water.
Limnological characteristics, eutrophication and cyanobacterial blooms in an inland reservoir, Australia
Authors: Rahman A. K. M. , Al Bakri Dhia , Ford Phillip , Church Tony
Published: December 2005

Ben Chifley Reservoir, the only potable water supply for Bathurst, New South Wales, Australia, has been experiencing recurrent cyanobacterial bloom problems since 1991. A study was undertaken from June 1998 to July 1999 to assess the limnological characteristics pertinent to eutrophication and the associated cyanobacterial blooms. From January–May 1999, the reservoir exhibited significant numbers of cyanobacterial cells, totalling > 9000 cells mL−1. The highest number of cells (> 27 000 cells mL−1) was recorded during April 1999. The water quality characteristics of the reservoir, and the river inflow and climatic data, were grouped into three distinct periods; before, during and after cyanobacterial blooms. High water temperature (15–22°C), thermal stratification (ΔT = 2.7–2.8°C), depletion of dissolved oxygen and high nutrient concentrations, all of which are conducive to enhanced cyanobacterial blooms, were evident before and during the bloom periods. Based on its nitrogen to phosphorus molar ratio, Ben Chifley Reservoir can be considered as being phosphorus‐deficient, in contrast to nitrogen, which is readily available from a number of sources in its drainage basin, including atmospheric fixation. Thus, it is recommended that adopting management strategies to reduce the quantity of bioavailable phosphorus in the reservoir would be the most effective way to minimize the occurrence of algal blooms.
RE‐READING INSCRIPTIONS IN CHINESE SCROLL PAINTING: THE ELEVENTH TO THE FOURTEENTH CENTURIES
Authors: HONGXING ZHANG
Published: December 2005

Art historians often regard Chinese art as the classic example of the unity between word and image. Such a view is predicated on the uncritical acceptance of canonical Chinese art theory and on mistaken notions about a changeless China and ideographic Chinese writing. Those misconceptions have prevented an understanding of the historical specificity of the relationship between the two graphic systems. In applying Charles Sanders Peirce's theory of the three fundamental types of sign (icon, index, symbol) to Chinese writing, scholars tend to conclude that it is not a symbolic‐indexic system, but primarily an iconic one.

Taking as the point of departure an antinomy between word and image, I demonstrate that the introduction of inscriptions into Chinese scroll painting was a long and uneven process. Between the eleventh and the fourteenth centuries, inscriptions initially entered pictorial space timidly; gradually growing in size and type, they eventually became separated from the pictorial elements, bringing about a fundamental change to the relations between word and image. In the age of the advent of codex and the invention of printing, inscriptions, through their intrusions into and encounters with painting, served to rescue the scroll from oblivion and to transform it into the major bearer of pictorial culture.
FAITH IN MATERIALS: CHRIST GIVING THE KEYS TO SAINT PETER BY JEAN‐AUGUSTE‐DOMINIQUE INGRES
Authors: SIEGFRIED SUSAN L.
Published: December 2005

This essay explores the larger ambitions and obsessions informing Ingres's Christ Giving the Keys to Saint Peter of 1820, which opens up a number of issues raised by religious art and, more broadly, by history painting in the nineteenth century: the relationship between narrative and iconic modes of representation; the generative role of close readings of textual and visual sources for pictorial invention; and the incongruous relationship between corporeality and incorporeality that was at the core of Christology. It examines the artist's attempt to lend substance to his pictorial motifs by going back to artefacts and historical evidence from the originary moment of Christian faith in ancient Rome. Ingres produced a modern religious art by working through, rather than against, the materialism of his age. This provoked a critical reaction against the painting that is examined for the light it sheds on a perceived conflict between the physical forms and spiritual content.