bluuebunny/crossref_metadata_2025 huggingface dataset:
Validated questionnaire on diagnosis and symptom severity for functional constipation in the Chinese population
Authors: CHAN A. O. O. , LAM K. F. , HUI W. M. , HU W. H. , LI J. , LAI K. C. , CHAN C. K. , YUEN M. F. , LAM S. K. , WONG B. C. Y.
Published: August 2005

Background : Functional constipation is a common problem in clinical practice. No validated questionnaire is available in Chinese.

Aim : To develop a validated questionnaire for diagnosis and symptom assessment in functional constipation for the Chinese population.

Methods : One hundred and eleven patients with constipation and 110 healthy controls were presented with a 24‐item constipation questionnaire in the Chinese language. Quality of life in constipation patients was assessed by Short Form‐36. Polyethylene glycol was prescribed, for 4 weeks, to 20 patients with newly diagnosed constipation. The questionnaire was administered before and 4 weeks after treatment. Concept, content, construct, discriminant validity and reliability of the questionnaire were assessed.

Results : Six items were selected by logistic regression to account for most of the differences between controls and constipated patients with a good reproducibility and internal consistency. A cut‐off score of ≥5 was determined to discriminate between controls and constipated patients with a sensitivity of 91% and a specificity of 91%. The constipation questionnaire correlated negatively with seven domains of the Short Form‐36 and discriminated between constipated patients who reported symptomatic improvement during polyethylene glycol treatment.

Conclusions : The Chinese constipation questionnaire could be used in epidemiological studies to assess the frequency and severity of constipation in patient populations and in interventional studies of constipation.
The 13C‐caffeine breath test distinguishes significant fibrosis in chronic hepatitis B and reflects response to lamivudine therapy
Authors: PARK G. J.‐H. , KATELARIS P. H. , JONES D. B. , SEOW F. , LIN B. P. C. , LE COUTEUR D. G. , NGU M. C.
Published: August 2005

Background : The 13C‐caffeine breath test is a non‐invasive, quantitative test of liver function.

Aim : To determine the utility of the 13C‐caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine.

Methods : Forty‐eight chronic hepatitis B virus patients and 24 controls underwent the 13C‐caffeine breath test. In 28 patients commenced on lamivudine, 13C‐caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy.

Results : Patients with Metavir F0–1 fibrosis (2.30 ± 1.02 Δ‰ per 100 mg caffeine) had a 13C‐caffeine breath test similar to controls (2.31 ± 0.85, P = 0.96). However, patients with F2–3 fibrosis (1.59 ± 0.78, P = 0.047) and cirrhotic patients (0.99 ± 0.33, P = 0.001) had a decreased 13C‐caffeine breath test. Fibrosis correlated best with the 13C‐caffeine breath test (rs = −0.62, P < 0.001). The 13C‐caffeine breath test independently predicted significant (F ≥ 2) and advanced (F ≥ 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 ± 0.04) for predicting advanced fibrosis. The 13C‐caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long‐term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated.

Conclusion : The 13C‐caffeine breath test distinguishes chronic hepatitis B virus‐related fibrosis and detects improvement in liver function in response to long‐term lamivudine.
Meta‐analysis: non‐pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic‐associated diarrhoea
Authors: SZAJEWSKA H. , MRUKOWICZ J.
Published: August 2005

Background : Antibiotic‐associated diarrhoea occurs in up to 30% of patients who receive antibiotics but can be prevented with probiotics.

Aim : To systematically evaluate the effectiveness of Saccharomyces boulardii in preventing antibiotic‐associated diarrhoea in children and adults.

Methods : Using medical subject headings and free‐language terms, the following electronic databases were searched for studies relevant to antibiotic‐associated diarrhoea and S. boulardii: MEDLINE, EMBASE, CINAHL and The Cochrane Library. Additional sources were obtained from references in reviewed articles. Only randomized‐controlled trials were considered for study inclusion.

Results : Of 16 potentially relevant clinical trials identified, five randomized‐controlled trials (1076 participants) met the inclusion criteria for this systematic review. Treatment with S. boulardii compared with placebo reduced the risk of antibiotic‐associated diarrhoea from 17.2% to 6.7% (RR: 0.43; 95% CI: 0.23–0.78; random effect model). The number needed to treat to prevent one case of antibiotic‐associated diarrhoea was 10 (95% CI: 7–16). No side‐effects were reported.

Conclusions : A meta‐analysis of data from five randomized‐controlled trials showed that S. boulardii is moderately effective in preventing antibiotic‐associated diarrhoea in children and adults treated with antibiotics for any reason (mainly respiratory tract infections). For every 10 patients receiving daily S. boulardii with antibiotics, one fewer will develop antibiotic‐associated diarrhoea.
Characterization of theCOMMD1(MURR1) mutation causing copper toxicosis in Bedlington terriers
Authors: Forman O. P. , Boursnell M. E. G. , Dunmore B. J. , Stendall N. , van de Sluis B. , Fretwell N. , Jones C. , Wijmenga C. , Rothuizen J. , van Oost B. A. , Holmes N. G. , Binns M. M. , Jones P.
Published: August 2005

Copper toxicosis is an autosomal recessive disorder affecting Bedlington terriers, characterized by elevated liver copper levels and early death of affected dogs. Genetic linkage mapping studies initially identified linkage between the disease and the microsatellite markerC04107. Subsequently, the deletion of exon 2 of thecopper metabolism domain containing 1(COMMD1) gene (formerlyMURR1) was shown to be the major cause of copper toxicosis, although the deletion breakpoints were not defined. In this investigation, polymerase chain reaction (PCR)‐based techniques and sequencing were used to isolate the deletion breakpoints, utilizing the newly available dog genome sequence. The breakpoints were positioned at 65.3091 and 65.3489 Mb of dog chromosome 10, in intron 1 and intron 2 ofCOMMD1respectively, a deletion of 39.7 kb. The two breakpoints share sequence homology suggesting that homologous recombination may have been responsible for the deletion. Using this information, a genomic diagnostic test for theCOMMD1deletion was developed and compared with microsatelliteC04107genotypes of 40 Bedlington terriers. Results from the 40 samples showed allele 2 ofC04107to be in linkage disequilibrium with theCOMMD1deletion.
Combination of multiple microsatellite data sets to investigate genetic diversity and admixture of domestic cattle
Authors: Freeman A. R. , Bradley D. G. , Nagda S. , Gibson J. P. , Hanotte O.
Published: August 2005

Microsatellite markers are commonly used for population genetic analyses of livestock. However, up to now, combinations of microsatellite data sets or comparison of population genetic parameters from different studies and breeds has proven difficult. Often different genotyping methods have been employed, preventing standardization of microsatellite allele calling. In other cases different sets of markers have been genotyped, providing differing estimates of population genetic parameters. Here, we address these issues and illustrate a general two‐step regression approach in cattle using three different sets of microsatellite data, to combine population genetics estimates of diversity and admixture. This regression‐based method is independent of the loci genotyped but requires common breeds in the data sets. We show that combining microsatellite data sets can provide new insights on the origin and geographical distribution of genetic diversity and admixture in cattle, which will facilitate global management of this livestock species.
A genome scan for loci affecting pork quality in a Duroc–Landrace F2 population
Authors: Rohrer G. A. , Thallman R. M. , Shackelford S. , Wheeler T. , Koohmaraie M.
Published: August 2005

A genome scan was conducted on 370 F2 Duroc–Landrace pigs. Microsatellite markers (n = 182) were genotyped across the entire F2 population, all F1 parents and the paternal grandparents. Breed of origin of all chromosomal segments inherited in F2 progeny were predicted using GenoProb, where genotypic data, genetic maps and extended pedigrees were used as inputs. Statistical tests for quantitative trait loci (QTL) associations were conducted on 41 phenotypes with SAS using output from GenoProb for genotypic data. Fixed effects included sex and age at slaughter. For certain analyses carcass weight, RYR1 genotype and/or PRKAG3 genotype were also included as covariates. Subjective and objective measures of pork colour, marbling and tenderness were recorded, as well as measures of carcass fatness and muscularity. Test results were adjusted to a genome‐wide level of significance. Five genomic regions presented significant evidence for QTL at chromosome 1 positions 6 cM (intramuscular fat) and 67 cM (Hunter L*), chromosome 2 position 62 cM (taste panel tenderness), chromosome 17 position 50 (loineye area and image analysis estimated loineye area) and X position 87 cM (carcass weight). Sixty‐six suggestive associations were detected. Fourteen of these associations were within the regions with significant QTL on chromosomes 2, 17 and X, and the remaining 52 associations resided in 29 other regions on 13 different chromosomes of the porcine genome. The chromosome 2 region of 60–66 cM was associated with all measures of pork tenderness and the region on chromosome 17 (32–39 cM) was associated with both measures of intramuscular fat and loineye area. After verification, the QTL for marbling and tenderness should be useful in commercial production to improve pork quality as the population was developed from two of the three most utilized breeds of swine in the USA.
Expression of C‐IAP1, C‐IAP2 and SURVIVIN discriminates different types of lymphoid malignancies
Authors: de Graaf Aniek O. , Han van Krieken J. , Tönnissen Evelyn , Wissink Willemijn , van de Locht Louis , Overes Ingrid , Dolstra Harry , de Witte Theo , van der Reijden Bert A. , Jansen Joop H.
Published: August 2005

(De‐)regulation of apoptosis plays an important role in normal and malignant lymphopoiesis. Apoptosis‐regulating genes of the BCL‐2 family and the recently identified inhibitors of apoptosis (IAP) family have been implicated in different types of non‐Hodgkin lymphoma (NHL). To investigate whether expression of specific apoptosis‐regulating genes correlated with different types of lymphoid malignancies, we measured the expression of five BCL‐2 family genes, four IAP family genes and SMAC by real‐time quantitative polymerase chain reaction in patient samples. In total, 137 samples from B‐ and T‐cell acute lymphoblastic leukaemia (ALL), B‐cell chronic lymphocytic leukaemia (CLL), six different NHL types and three control tissue types were analysed. The data were further analysed using cluster and discriminant analysis. Three specific expression patterns were identified for CLL, ALL and NHL respectively. CLL samples, as well as B‐ALL and follicular lymphoma samples showed high similarity in the expression of these apoptosis‐regulating genes and could be distinguished from each other and other diseases and controls. Discriminant analysis identified three members of the IAP family, C‐IAP1, C‐IAP2 and SURVIVIN, as the most informative genes to discriminate between these lymphoid malignancies.
GST genotype may modify clinical phenotype in patients with Fanconi anaemia
Authors: Davies Stella M. , Radloff Gretchen A. , DeFor Todd E. , Levran Orna , Batish Sat Dev , Hanenberg Helmut , Auerbach Arleen D.
Published: August 2005

In the search for genetic modifiers of the Fanconi anaemia (FA) phenotype, we examined the role of polymorphism in three glutathione s‐transferase genes (GSTT1, GSTM1 and GSTP1) in 356 FA patients enrolled in the International Fanconi Anaemia Registry (IFAR). Cellular sensitivity to 1,2:3,4 diepoxybutane was significantly increased in GSTT1 deleted compared with GSTT1 positive cases (median chromosomal breaks 11·1 vs. 8·3, P < 0·01) but there was no effect on clinical manifestations of FA. GSTM1 genotype significantly influenced time to bone marrow failure in complementation group FA‐C, (median age 3·0 years vs. 7·0 years, P < 0·01). GSTP1 genotype did not influence FA phenotype.
Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta‐analysis of randomised‐controlled trials
Authors: Vardakas Konstantinos Z. , Michalopoulos Argyris , Falagas Matthew E.
Published: August 2005

Fluconazole and itraconazole are used as antifungal prophylaxis in neutropenic patients with haematological malignancies. A meta‐analysis of randomised‐controlled trials (RCTs) was performed in order to compare their safety and effectiveness in this population. Data were obtained from PubMed, Current Contents, Cochrane Central Register for Controlled Trials and references from relevant articles. Five RCTs were included in the analysis. Publication bias and statistically significant heterogeneity was not observed among the analysed studies. Fewer patients were withdrawn due to the development of adverse effects associated with fluconazole when compared with itraconazole [odds ratio (OR) = 0·27, 95% confidence interval (CI): 0·18–0·41]. On the contrary, prophylactic use of fluconazole resulted in significantly more fungal infections (documented and suspected infections combined, OR = 1·62, 95% CI: 1·06–2·48). There were no statistically significant differences regarding documented fungal infections (OR = 1·51, 95% CI: 0·97–2·35), invasive fungal infections (OR = 1·44, 95% CI: 0·96–2·17), overall mortality (OR = 0·89, 95% CI: 0·63–1·24) and mortality attributed by the authors to fungal infections (OR = 1·30, 95% CI: 0·75–2·25) between the two medications. These data suggest that, even though itraconazole is more effective than fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies, the development of more adverse effects may limit its use.
Azithromycin reduces Chlamydia pneumoniae‐induced attenuation of eNOS and cGMP production by endothelial cells
Authors: Bouwman J. J. M. , Visseren F. L. J. , Bevers L. M. , Van Der Vlist W. E. , Bouter K. P. , Diepersloot R. J. A.
Published: August 2005

Background  Intracellular infections with cytomegalovirus (CMV) or Chlamydia pneumoniae (Cp) may play a role in the aetiology of atherosclerosis. Nitric oxide (NO) is a key regulator of endothelial function. Under pathological conditions uncoupling of endothelial nitric oxide synthase (eNOS) leads to vessel damage as a result of production of oxygen radicals instead of NO. We hypothesized that infection‐induced atherosclerosis is initiated by changes in NO metabolism and may be reversed by azithromycin treatment.

Methods  Confluent human umbilical vein endothelial cells (HUVECs) were infected with Cp or CMV. After 48 h of infection, production of eNOS, cyclic guanosine monophosphate (cGMP) and reactive oxygen species (ROS) was measured. Detection of cGMP was used as a reporter assay for the bioavailability of NO. Subsequently, Cp‐ and CMV‐infected HUVECs were coincubated with 0·016 mg L−1 and 1 mg L−1 azithromycin.

Results  Infection with Cp (MOI 1 and MOI 0·1) and CMV (MOI 1) caused a dose‐ and time‐dependent reduction of eNOS production in the HUVECs: Cp MOI 1: 1141 ± 74 pg mL−1 (P < 0·01); Cp MOI 0·1: 3189 ± 30 pg mL−1 (P < 0·01); CMV: 3213 ± 11 pg mL−1 (P < 0·01) vs. 3868 ± 83 pg mL−1 for uninfected HUVECs. Chlamydia pneumoniae– but not CMV‐infection also reduced cGMP‐production (Cp: 0·195 ± 0·030 pmol mL−1 (P < 0·01); CMV: 0·371 ± 27 pmol mL−1 (P > 0·05) vs. 0·378 ± 0·019 pmol mL−1 for uninfected HUVECs). CMV‐infection did not affect ROS production either, but Cp‐infection reduced ROS‐production by 21% (P > 0·05; Cp MOI 0·1) to 68% (P < 0·01; Cp MOI 1). Azithromycin treatment restored Cp‐induced eNOS, cGMP and ROS production in a dose‐dependent manner.

Conclusions  Infection with Cp in endothelial cells in vitro attenuates eNOS, cGMP and ROS production in HUVECs and azithromycin reverses Cp‐induced effects on eNOS, cGMP and ROS‐production. The results from our in vitro research support the role of antibiotic therapy for infection‐induced atherosclerosis by indicating that azithromycin does actually improve endothelial function.
Glucagon‐like peptide‐1 reduces the pulsatile component of testosterone secretion in healthy males
Authors: Jeibmann A. , Zahedi S. , Simoni M. , Nieschlag E. , Byrne M. M.
Published: August 2005

Background  Glucagon‐like‐peptide‐1 (7–36) amide (GLP‐1), a potent regulator of glucose homeostasis, has been implicated in the control of hypothalamic‐pituitary function. In vivo it is a relevant neuroendocrine modulator of gonadotropin‐releasing hormone release, suggesting its possible role as a metabolic signal to the reproductive system. The present study was undertaken to establish its effect on luteinizing hormone (LH) and testosterone secretion in nine healthy male volunteers.

Materials and methods  Each subject underwent an oral glucose tolerance test to establish LH, testosterone, and GLP‐1 responses to glucose. Euglycaemic clamp experiments (6 h) were performed on two occasions with saline or with a constant infusion of GLP‐1 (0·4 pmol kg−1 min −1). Blood samples were drawn at 10‐min intervals to measure the pulsatile pattern of LH and testosterone secretion.

Results  Ingestion of oral glucose resulted in a reduction in plasma testosterone levels at 30 min compared with baseline (P < 0·004) despite unaltered LH levels (P = 0·5). Constant GLP‐1 infusion resulted in no change in LH (P = 0·83), testosterone (P = 0·96), follicle stimulating hormone (FSH) (P = 0·86) and leptin levels (P = 0·3). Pulse analysis revealed no significant difference in the number (P = 0·1) or median absolute amplitude (P = 0·3) of the LH pulses. However, there was a significant decrease in the number (3·0 ± 0·6 vs. 1·3 ± 0·4; P < 0·05) and a tendency for increased duration of testosterone pulses (97·4  16·7 vs. 170  27·1 min; P = 0·06).

Conclusion  Oral glucose ingestion and intravenous GLP‐1 infusion reduce the pulsatile component of testosterone secretion by a mechanism independent of LH release.
Plasma matrix metalloproteinase‐3 level is an independent prognostic factor in stable coronary artery disease
Authors: Wu T. C. , Leu H. B. , Lin W. T. , Lin C. P. , Lin S. J. , Chen J. W.
Published: August 2005

Background  Recent evidence suggests the important role of matrix metalloproteinases (MMPs) in the progression of atherosclerosis and development of clinical events. We assessed the prognostic value of different plasma MMPs in patients with stable coronary artery disease (CAD).

Materials and methods  A total of 165 consecutive nondiabetic patients with angiographically significant CAD (n = 150) or normal coronary angiograms despite exercise‐induced myocardial ischemia (cardiac syndrome X, n = 15) and 17 normal subjects were evaluated. In each subject, plasma inflammatory markers including high sensitivity C‐reactive protein (hsCRP) and MMP‐2, 3 and 9 were measured. In CAD patients, major cardiovascular events including cardiac death, nonfatal myocardial infarction, unscheduled coronary revascularization and hospitalization as a result of unstable angina were prospectively followed up for more than 6 months.

Results  Plasma levels of MMPs were significantly higher in CAD patients than in those with cardiac syndrome X and in normal subjects (MMP‐2: 914·76 ± 13·20 vs. 830·79 ± 31·95 vs. 783·08 ± 28·40 ng mL−1, P = 0·002; MMP‐3: 129·59 ± 4·21 vs. 116·86 ± 8·09 vs. 91·71 ± 9·55 ng mL−1, P = 0·011; MMP‐9: 31·42 ± 2·84 vs. 11·40 ± 5·49 vs. 6·71 ± 2·89 ng mL−1, P = 0·006). In CAD patients, there were 48 major cardiovascular events during a mean follow‐up period of 17·74 ± 0·85 months. The numbers of diseased vessels (HR = 2·19, 95% CI 1·20–1·02, P = 0·011), plasma hsCRP (HR = 2·21, 95% CI 1·18–4·11, P = 0·013) and MMP‐3 level (HR = 2·46, 95% CI = 1·15–5·28, P = 0·021) were associated with the development of cardiovascular events. However, only the plasma MMP‐3 level was an independent predictor of the adverse events in CAD patients (HR = 2·47, 95% CI 1·10–5·54, P = 0·028).

Conclusions  Plasma MMP levels were increased in CAD patients. Plasma MMP‐3 level, rather than hsCRP, was an independent prognostic marker for future cardiovascular events, suggesting its potential role in risk stratification and clinical management of stable CAD.
Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia
Authors: Ter Avest E. , Abbink E. J. , De Graaf J. , Tack C. J. , Stalenhoef A. F. H.
Published: August 2005

Background  By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity.

Methods  In a double‐blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 ± 7 years) were randomized to rosuvastatin 40 mg day−1 or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic–hyperinsulinaemic clamp after 12 weeks of both treatment periods.

Results  Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides −28%; LDL‐c −50%; VLDL‐c −56%, VLDL‐TG −39%) and both parameters of low‐grade inflammation (as measured by hsCRP, −16%) and oxidative stress (as measured by plasma‐oxLDL, −55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41·7 ± 17·4 vs. 40·6 ± 11·1 L kg−1 min−1, placebo vs. rosuvastatin, P = 0·71).

Conclusion  Despite marked improvements in lipid and lipoprotein values, low‐grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH.
Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance
Authors: Wascher T. C. , Schmoelzer I. , Wiegratz A. , Stuehlinger M. , Mueller‐Wieland D. , Kotzka J. , Enderle M.
Published: August 2005

Objectives  To investigate whether selective reduction of postchallenge hyperglycaemia influences acute endothelial dysfunction, a very early manifestation of vascular disease, in patients with impaired glucose tolerance.

Methods  In a randomized, double‐blind, placebo‐controlled, cross‐over study the acute effect of 200‐mg acarbose was investigated in 28 subjects with diagnosed impaired glucose tolerance. Flow‐mediated dilation (FMD) of the brachial artery was determined as a measure of endothelial function before and 2 and 3 h after ingestion of 100‐g saccharose. Asymmetrical dimethylarginine (ADMA) was measured by high‐performance liquid chromatography.

Results  A negative correlation was observed between the changes of glucose and FMD (r = 0·416, P = 0·0018) 2 h after ingestion of saccharose. At 3 h, neither blood glucose nor FMD were different from baseline. Changes of both blood glucose (P = 0·0007) and FMD (P = 0·046) were significantly lower after administration of acarbose. Subgroup analysis revealed that the effect of acarbose was restricted to those subjects with an increase of blood glucose above the median increase of glycaemia. No changes of plasma ADMA were observed.

Conclusions  Our data clearly demonstrate that the postchallenge alteration of vascular function in patients with impaired glucose tolerance is caused by the acute elevation of glycaemia but not mediated by ADMA.
Morin sulphates/glucuronides enhance macrophage function in microgravity culture system
Authors: Hsieh C.‐L. , Chao P.‐D. L. , Fang S.‐H.
Published: August 2005

Background  The immune system changes significantly in astronauts during and after space flight. Although the mechanism has not been defined, it is reasonable to begin developing effective countermeasures to the physiological consequences of spaceflight, especially immunosuppression. Many studies have been published about the effect of flavonoids on immune modulation. Thus, the aim of this study was to develop whether flavonoids could be the effective countermeasures to the immunosuppression caused by microgravity.

Materials and methods  We used a rotating wall vessel 3D (three‐dimensional) culture system which recreates some of the culture conditions that occur during microgravity to study the effects of microgravity on the function of macrophages and assess the modulating effects of flavonoids on microgravity‐induced macrophage dysfunction.

Results  We demonstrated 65% and 80% reduction in mitogen‐induced nitric oxide and cytokine production of 3D‐cultured macrophages, compared to conventional two‐dimensional (2D)‐cultured cells. Moreover, the microgravity‐induced macrophage dysfunction was not restored by transferring cells from 3D to 2D culture. However, the addition of morin sulphates/glucuronides in 3D culture compensated for the loss of macrophage function.

Conclusion  The result presented here suggests for the first time that an immune‐modulatory strategy using flavonoid supplements such as morin would benefit the health of astronauts.
Seasonal response of nutrients to reduced phosphorus loading in 12 Danish lakes
Authors: SØNDERGAARD MARTIN , JENSEN JENS PEDER , JEPPESEN ERIK
Published: August 2005

1. Concentrations of phosphorus, nitrogen and silica and alkalinity were monitored in eight shallow and four deep Danish lakes for 13 years following a phosphorus loading reduction. The aim was to elucidate the seasonal changes in nutrient concentrations during recovery. Samples were taken biweekly during summer and monthly during winter.

2. Overall, the most substantive changes in lake water concentrations were seen in the early phase of recovery. However, phosphorus continued to decline during summer as long as 10 years after the loading reduction, indicating a significant, albeit slow, decline in internal loading.

3. Shallow and deep lakes responded differently to reduced loading. In shallow lakes the internal phosphorus release declined significantly in spring, early summer and autumn, and only non‐significantly so in July and August. In contrast, in deep lakes the largest reduction occurred from May to August. This difference may reflect the much stronger benthic pelagic‐coupling and the lack of stratification in shallow lakes.

4. Nitrogen only showed minor changes during the recovery period, while alkalinity increased in late summer, probably conditioned by the reduced primary production, as also indicated by the lower pH. Silica tended to decline in winter and spring during the study period, probably reflecting a reduced release of silica from the sediment because of enhanced uptake by benthic diatoms following the improved water transparency.

5. These results clearly indicate that internal loading of phosphorus can delay lake recovery for many years after phosphorus loading reduction, and that lake morphometry (i.e. deep versus shallow basins) influences the patterns of change in nutrient concentrations on both a seasonal and interannual basis.
Heterodimerization with LBP‐1b is necessary for nuclear localization of LBP‐1a and LBP‐1c
Authors: Sato Fuyuhiko , Yasumoto Ken‐ichi , Kimura Kota , Numayama‐Tsuruta Keiko , Sogawa Kazuhiro
Published: August 2005

The LBP‐1 family consists of four proteins, which act as transcription factors in the formation of dimers with a member of this family. LBP‐1a and LBP‐1b are splicing variants from one gene, and LBP‐1c and LBP‐1d also arise from the alternative splicing of another gene. Investigation of subcellular localization of LBP‐1 proteins fused to YFP revealed that the LBP‐1b was localized in the nucleus, whereas LBP‐1a and LBP‐1c were exclusively localized in the cytosol. The peptide of 36 amino acids encoded by exon 6, a specific exon used only for LBP‐1b, possessed the function of a nuclear localization signal (NLS). Nuclear localization of LBP‐1a and LBP‐1c occurred when LBP‐1b was co‐expressed, suggesting that heterodimerization of LBP‐1a and LBP‐1c with LBP‐1b is important for their nuclear transport. Transiently expressed LBP‐1 proteins in COS‐7 cells formed speckles in the nucleus. Most speckles overlapped with the PML body. The activity of LBP‐1a for accumulation in the PML body was mapped in the N‐terminal region.
Systematic search for the Cra‐binding promoters using genomic SELEX system
Authors: Shimada Tomohiro , Fujita Nobuyuki , Maeda Michihisa , Ishihama Akira
Published: August 2005

Cra (or FruR), a global transcription factor with both repression and activation activities, controls a large number of the genes for glycolysis and gluconeogenesis. To get insights into the entire network of transcription regulation of the E. coli genome by Cra, we isolated a set of Cra‐binding sequences using an improved method of genomic SELEX. From the DNA sequences of 97 independently isolated DNA fragments by SELEX, the Cra‐binding sequences were identified in a total of ten regions on the E. coli genome, including promoters of six known genes and four hitherto‐unidentified genes. All six known promoters are repressed by Cra, but none of the activation‐type promoters were cloned after two cyles of SELEX, because the Cra‐binding affinity to the repression‐type promoters is higher than the activation‐type promoters, as determined by the quantitative gel shift assay. Of a total of four newly identified Cra‐binding sequences, two are associated with promoter regions of the gapA (glyceraldehyde 3‐phosphate dehydrogenase) and eno (enolase) genes, both involved in sugar metabolism. The regulation of newly identified genes by Cra was confirmed by the in vivo promoter strength assay using a newly developed TFP (two‐fluorescent protein) vector for promoter assay or by in vitro transcription assay in the presence of Cra protein.
Intracranial haemorrhages in French haemophilia patients (1991–2001): clinical presentation, management and prognosis factors for death
Authors: Stieltjes N. , Calvez T. , Demiguel V. , Torchet M. F. , Briquel M. E. , Fressinaud E. , Claeyssens S. , Coatmelec B. , Chambost H. ,   The French ICH Study Group
Published: August 2005

Summary.  Intracranial haemorrhage (ICH) is known to be a severe although uncommon complication of haemophilia. A national survey has been conducted in France in order to collect information about ICHs which occurred in haemophiliacs between 1991 and 2001 and to propose recommendations for the diagnostic and treatment of ICH. Within this period, 123 episodes of ICH were recorded from 106 patients. Two‐thirds of ICH concerned patients with severe haemophilia. Half of the cases occurred in patients under 15 years of age, 67.2% of which were post‐traumatic. Ten cases occurred in neonates with three fatal outcomes. Overall mortality was high (21.9%) suggesting that availability of clotting factor concentrates has not improved the prognosis of this event. Morbidity was also high with 60% of long‐term sequelae. The following parameters have been identified as prognostic factors for death: thrombocytopenia, HCV infection, intraventricular or intraparenchymatous haemorrhage. A delay in diagnosis was mentioned in 43.3% of cases, often related to the lack of recognition of the initial symptoms, which may be very common (apathy, tearfulness in young children and headache in elder patients). Delayed replacement therapy was recorded in 37.2% of cases. Emergency units initially dealt with half of these patients. Information concerning recognition and management of these episodes, not only in severe haemophilia, but also in moderate and mild forms, should be regularly supplied to paediatricians in maternity and physicians from emergency units, as well as to patients and their relatives.
Iliopsoas haemorrhage in patients with haemophilia: results from one centre
Authors: Balkan C. , Kavakli K. , Karapinar D.
Published: August 2005

Summary.  Iliopsoas haematoma is a well‐recognized complication of haemophilia, and is considered as potentially life threatening and significantly associated with morbidity. There are only rare reports on the incidence or outcomes of iliopsoas bleeding since the widespread usage of modern therapies for haemophilia. In this study, we present the experience of Ege University Haemophilia Centre with iliopsoas bleeding and its early and late complications. We reviewed 146 haemophiliacs (106 haemophilia A, 40 haemophilia B). Fourteen iliopsoas bleeding episodes were identified in eight haemophiliacs. Three patients (37%) had one episode, four (50%) had two episodes and one (13%) had three episodes. Two patients had a high titre inhibitor against factor VIII and accounted for three bleeding episodes (21%). We did not observe any episodes in six patients receiving prophylaxis. Iliopsoas haematomas were confirmed by ultrasonography in all patients. In physical examination, the most common symptoms were thigh, hip and groin pain, hip flexion contracture, abdominal tenderness and paraesthesia in the distribution of the femoral nerve. The mean duration of therapy with clotting factor concentrate was 7.8 ± 1.6 days. The mean duration of hospitalization was 4.8 ± 2.0 days. All patients started to receive a physical therapy program 6.0 ± 2.4 days after the initiation of haemostatic therapy which lasted 20.0 ± 6.0 days. Ultrasonographic findings related to iliopsoas haematoma disappeared in all patients within 3 months from the initial episodes. Only in one patient with mild haemophilia A, heterotopic bone formation (myositis ossificans) developed as a long‐term complication. In conclusion, pain around the hip joint, femoral neuropathy and hip flexion contracture in a patient with haemophilia should alert the physician to the possibility of an iliopsoas haematoma. Early and effective factor replacement therapy is essential in the prevention of the complications.
Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed
Authors: van Dijk K. , Fischer K. , van der Bom J. G. , Grobbee D. E. , van den Berg H. M.
Published: August 2005

Summary.  To quantify variation in clinical phenotype of severe haemophilia we performed a single centre cohort study among 171 severe haemophilia patients. Age at first joint bleed, treatment requirement (i.e. annual clotting factor use), annual bleeding frequency and arthropathy were documented. Because treatment strategies intensified during follow‐up, patients were stratified in two age groups: patients born 1968–1985 (n = 91), or 1985–2002 (n = 80). A total of 2166 patient‐years of follow‐up were available (median 12.0 years per patient). Age at first joint bleed ranged from 0.2 to 5.8 years. Patients who had their first joint bleed later needed less treatment and developed less arthropathy. In patients born 1968–1985 during both on‐demand and prophylactic treatment, the 75th percentile of annual joint bleed frequency was consistently four times as high as the 25th percentile. In both age groups variation in annual clotting factor use between 25th and 75th percentiles was 1.4–1.5 times for prophylaxis and 3.8 times for on‐demand treatment. To conclude, the onset of joint bleeding is inversely related with treatment requirement and arthropathy and may serve as an indicator of clinical phenotype. Thus, providing a starting point for aetiological research and individualization of treatment.
Spontaneous major bleeding in acquired factor X deficiency secondary to AL‐amyloidosis
Authors: Enjeti A. K. , Walsh M. , Seldon M.
Published: August 2005

Summary.  Abnormal bleeding may be seen in up to a third of patients with amyloidosis. Factor X deficiency is the commonest acquired coagulopathy in amyloidosis. While mild intracutaneous bleeding is common, spontaneous life‐threatening haemorrhage is rare. We report a case of acquired FX deficiency due to amyloid light chain (AL)‐amyloidosis presenting with spontaneous retroperitoneal bleeding. The diagnostic and management issues in this patient are discussed.
National haemophilia programme development in the Republic of Georgia
Authors: Kirtava A. , Soucie M. , Evatt B. , Mdivinishvili M. , Abashidze M. , Iosava G.
Published: August 2005

Summary.  After the dissolution of Soviet Union in 1991, haemophilia care in the Republic of Georgia was negatively affected because of the expense of treatment products, lack of clinical and diagnostic facilities, and the need for trained personnel throughout the country. In 2001, the Georgian Government, working through the Ministry of Health, in collaboration with Georgian Association of Haemophilia and Donors, the Institute of Haematology and Transfusion, and the World Federation of Haemophilia, initiated a National Haemophilia Programme. As part of this programme the first Georgian Haemophilia Treatment Centre (HTC) was established. In this paper, we will describe (i) our outreach efforts to identify patients with haemophilia (PWH), (ii) the diagnostic and clinical services provided to patients by the HTC, and (iii) the results of a patient survey designed to assess patient satisfaction with the care provided. Total of 216 PWH were diagnosed, mean age was 25 years (range 4 months to 75 years); 43% had severe, 33% had moderate and 24% had mild haemophilia A or B. Overall, 183 (85%) had haemophilia A and 33 (15%) had haemophilia B, giving a ratio of 5.6. During the 2‐year period, 77% of the expected number of PWH was identified by our outreach programme. Vast majority had comprehensive evaluation including joint assessment and over 60% were tested for blood‐borne infections within a year and half period. Our findings showed that haemophilia care was considerably improved since the beginning of the National Haemophilia Programme and the survey of PWH showed a high degree of satisfaction with services provided in the HTC. In conclusion, close collaboration of the government, non‐government entities and medical professionals in a Georgian national haemophilia care model; resulted in the successful delivery of the much needed services and care to the people living in Georgia with haemophilia.
Stability of lyophilized and reconstituted plasma/albumin‐free recombinant human factor VIII (ADVATE rAHF‐PFM)
Authors: Parti R. , Schoppmann A. , Lee H. , Yang L.
Published: August 2005

Summary.  Traditionally the serum protein albumin has been used to stabilize lyophilized recombinant factor VIII (rFVIII) products. Advanced rFVIII products have now been developed that employ other stabilizers. ADVATE antihaemophilic factor (recombinant), plasma/albumin‐free method (rAHF‐PFM) utilizes trehalose and mannitol as stabilizers in the lyophilized preparation. An extensive in vitro evaluation was conducted on the stability of rAHF‐PFM as measured by retained activity over time. Both lyophilized and reconstituted rAHF‐PFM were analysed, and the full range of available potencies were tested under varying temperature conditions. Lyophilized rAHF‐PFM exhibited a high degree of stability under a range of conditions. The mean retained activity of 15 rAHF‐PFM lots (ranging from low to maximal potency) at 5 °C for 30 months was 91.6% (95% CI, 88.9–94.3%) of initial potency. rAHF‐PFM also remained highly stable after storage at room temperature for 18 months, with 82.0% (95% CI, 79.2–84.9%) of initial activity retained at 25 °C and 79.1% (95% CI, 76.2–81.9%) at 30 °C. All other parameters, including moisture, appearance, solubility, pH and aggregation remained within the established product specifications. The mean retained activity after 1 month of storage at 40 °C was 94.0% (95% CI, 92.4–95.6%). A high temperature excursion to 40 °C for 2 weeks did not compromise subsequent stability of the lyophilized powder either under refrigeration or at room temperature. Reconstituted samples from 11 rAHF‐PFM lots retained an average of 92.0% (95% CI, 89.8–94.3%) activity after 24 h. The present study provides evidence of good stability at differing temperatures of an albumin‐free formulated rFVIII product.
A postmarketing surveillance study of the safety and efficacy of ReFacto® (St Louis‐derived active substance) in patients with haemophilia A
Authors: Smith M. P. , Giangrande P. , Pollman H. , Littlewood R. , Kollmer C. , Feingold J. ,   The Refacto St Louis Study Group
Published: August 2005

Summary.  This clinical trial evaluated the safety and efficacy of ReFacto (St Louis‐derived active substance) in patients with severe or moderately severe haemophilia A over a period of 6 months or 50 exposure days (EDs), whichever occurred first. Sixty patients, 58 previously treated and two previously untreated, were enrolled into this study. This was an open‐label, multicentre, postmarketing surveillance study in which patients received prophylaxis or on‐demand treatment as determined by their doctor. Surgical prophylaxis was evaluated in seven patients requiring elective surgery. Thirty‐two patients aged <1 to 66 years (median 19.5) received prophylaxis and 28 patients, aged 1–71 years (median 33.5), received on‐demand treatment. The majority of patients had severe haemophilia A (FVIII:C < 2%): 84.4% in the prophylaxis group and 85.7% in the on‐demand group. Prophylaxis with ReFacto was associated with a median of 6.7 bleeds per year (range: 0–37). The investigator's assessment of final outcome for prophylactic treatment was excellent or effective for 93.1% of patients. ReFacto resolved 92.8% of bleeds with one or two infusions. The investigator's assessment was excellent or good for 98.2% of bleeds treated with ReFacto. Haemostasis was achieved for all seven surgical cases and ReFacto gave an excellent or good response for each. The nature and incidence of adverse events was as expected and no new safety concerns emerged. One previously treated patient (PTP) developed a high‐titre inhibitor (maximum 75 BU) and one minimally treated patient (MTP) developed a low‐titre inhibitor while on the study but eventually achieved high titres (maximum 30 BU) after immune tolerance therapy was initiated with a plasma‐derived FVIII product. One previously untreated patient (PUP) developed a transient low‐titre inhibitor (0.4 BU). Other serious adverse events (SAEs) were unrelated to study treatment. There were no allergic events. The results of this study are consistent with the previously published ReFacto pivotal studies.
Dental procedures in adult patients with hereditary bleeding disorders: 10 years experience in three Italian Hemophilia Centers
Authors: Franchini M. , Rossetti G. , Tagliaferri A. , Pattacini C. , Pozzoli D. , Lorenz C. , Del Dot L. , Ugolotti G. , Dell'Aringa C. , Gandini G.
Published: August 2005

Summary.  Excessive bleeding after dental procedures are one of the most frequent complications occurring in patients with hereditary bleeding disorders. In this retrospective study we collected data from 10 years of experience in the oral care of patients with congenital haemorrhagic disorders in three Italian Hemophilia Centers. Between 1993 and 2003, 247 patients with inherited bleeding disorders underwent 534 dental procedures including 133 periodontal treatments, 41 conservative dentistry procedures, 72 endodontic treatments and 288 oral surgery procedures. We recorded 10 bleeding complications (1.9%), most of which occurred in patients with severe/moderate haemophilia A undergoing multiple dental extractions. Thus, our protocol of management of patients with hereditary bleeding tendency undergoing oral treatment or surgery has been shown to be effective in preventing haemorrhagic complications.
Intracranial haemorrhage in severe haemophilia: prevalence and outcome in a developing country
Authors: Ghosh K. , Nair A. P. , Jijina F. , Madkaikar M. , Shetty S. , Mohanty D.
Published: August 2005

Summary.  Intracranial haemorrhage (ICH) is a common cause of morbidity and mortality in haemophilic patients all over the world. From 1995 to 2004, we have investigated 37 patients with 43 episodes of ICH at our Comprehensive Haemophilia Care Center from a total of 600 registered patients. Diagnosis of ICH in the patients was confirmed by clinical, haematological and computed tomographic imaging data. Three patients died despite replacement therapy while one child who had a ventriculo‐atrial shunt for acute hydrocephalus also died before further intervention. One of the four patients who died also had severe aplastic anaemia for 6 years in addition to severe haemophilia. Detailed history obtained from 143 families with haemophilia attending the Genetic Diagnosis Clinic at our Center showed a positive history of cerebral bleed in 39 episodes in 37 patients. Sixteen families gave a history of death in the family of haemophilic patients due to ICH, while in the remaining 21 families, the patients had survived the episode after treatment elsewhere. However, the ICH was not confirmed by image data in these cases. The treatment protocols were also not available in these cases. Conservative factor replacement therapy 100% correction for 3 days followed by 50–60% correction for 7 days) coupled with the epsilon amino caproic acid, the antifibrinolytic agent at least for 30 days led to a mortality (10.8%) similar to that of the western countries and almost no morbidity. Surgery was not required in any of these patients except in one elderly patient with HIV infection on antiretroviral therapy.
The use of a disability model in haemophilia research
Authors: van Genderen F. R. , van Meeteren N. L. U. , Heijnen L. , van den Berg H. M. , Helders P. J. M.
Published: August 2005

Summary.  Most haemophilia research is medically orientated. However, assessment of the impact of disease on the individual is different when viewed from a rehabilitation perspective. Several models are available to explore functioning and health from this perspective. The disablement process (DP) is such a model, and the aim of this study was to introduce this process in haemophilia research to see whether this type of research could lead to meaningful data. Forty‐three adult patients with severe haemophilia participated in this study in which the three ‘main pathway’ domains of the DP (impairments, functional limitations and disability) and two additional factors (intra‐individual and risk factors) were addressed. Three questionnaires (HAL, Dutch‐AIMS2 and IPA) were incorporated, and Pettersson scores for 21 patients were retrieved. Step‐wise and hierarchical regression analysis was used to assess relationship between the various domains. Arthropathy explained 48% of the variance in functional limitations and nearly 25% of the variance in disability. Functional limitations explained 54% of the variance in disability. Patients identified pain as an important aspect of health which addressed 22% and 13% of the variance in functional limitations and disability respectively. Age was correlated with arthropathy (r = 0.85; P < 0.001), whereas psychological health correlated with pain (r = 0.67; P < 0.001). Both variables were also correlated with functional limitations and disability. Analyses adjusting for the effects of age and psychological health were subsequently performed resulting in more insight in the associations within the DP. The use of the DP in haemophilia research proved to be useful.