bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of body surface area in atopic dermatitis using specific PC software (ScoradCard©)
Authors: Tripodi Salvatore , Panetta Valentina , Pelosi Simone , Pelosi Umberto , Boner Attilio L.
Published: December 2004

In skin diseases, evaluation of involved surface area is a crucial factor in grading the degree of severity. We examined the reliability of body surface area assessment and relative inter‐observer and intra‐observer variability using new software (ScoraCard©), specifically designed to evaluate automatically the extension of the involved area in the SCORAD index. Twenty pediatricians, untrained in the evaluation of skin disease, estimated the percentage of surface area involved in photo‐tests of two children with artificial well‐delimited lesions, at first by sight and then through software. As ‘gold standard’ the exact amount of pixels was counted for the whole body surface of the children, for the different body zones and for the painted artificial lesions, expressed as percentage of the respective zone. For photo 1, gold standard was 38.06% and median percentage was 43.44% (95% CI 40.7–46.21) by sight (p = 0.002) and 37.99% (95% CI 36.04–39.94) by ScoradCard (p = 0.79). For photo 2, gold standard was 27.84%, median percentage was 30.44% (95% CI 28.25–32.63) by sight (p = 0.047) and 27.8% (95% CI 26.55–29.04) by ScoradCard (p = 0.79). The level of agreement (kappa statistic), cumulative for the two photo tests, was 0.38 (fair agreement) by sight method and 0.67 (good agreement) by ScoradCard©. Among the 10 pediatricians who repeated the computer aided evaluation 3 months apart, the intra‐observer variability was not significantly different: the median percentage was 31.5% (95% CI 27.0–49.4) at time 0 and 29.0% (95% CI 26.7–47.2) 3 months later (p = 0.76). This new software could be a useful tool in evaluating skin lesions extension, minimizing inter‐ and intra‐observer variability, which is an important goal in multi‐centre studies.
Correlation of nitrites in breath condensates and lung function in asthmatic children
Authors: Straub Daniel A. , Ehmann Rainer , Hall Graham L. , Mœller Alexander , Hamacher Jürg , Frey Urs , Sennhauser Felix H. , Wildhaber Johannes H.
Published: December 2004

We aimed to evaluate the value of exhaled breath condensates in monitoring airway inflammation in childhood asthma before and after high altitude climate therapy.

Forty‐eight asthmatic children on regular anti‐asthma treatment with a normal FEV1and positive skin prick test for house dust mites were recruited. All children had been referred to an alpine clinic for high altitude climate therapy, because of persistent asthmatic symptoms despite use of daily anti‐inflammatory treatment. Subjects were assessed on their arrival and before departure from the alpine clinic. Spirometry, bronchial provocation tests and measurements of nitrites in breath condensates were performed.

Median levels of nitrites were significantly higher before than after high altitude climate therapy (1.27 vs. 0.93 μm; p = 0.008). In addition, MEF50improved significantly (p < 0.0005). There was a significant correlation between nitrites in breath condensates and MEF50(r = −0.63, p < 0.0001), symptoms (r = 0.47, p = 0.0007) and airway hyper‐reactivity (AHR) (r = −0.41, p = 0.004).

In summary, we found a reduction in nitrites in breath condensates after a high altitude climate therapy. Significant correlations were found between nitrites and MEF50, AHR and symptoms. We conclude that the measurement of nitrites may be feasible to objectively assess airway inflammation in asthmatic children in order to detect ongoing inflammation in children with normal FEV1but persistent symptoms.
Commercial fishing in the Brazilian Amazon: regional differentiation in fleet characteristics and efficiency
Authors: Almeida O. T. , Lorenzen K. , Mcgrath D. G.
Published: December 2004

Regional differentiation in fleet characteristics and economic efficiency, as well as the total elasticity of scale in the commercial fishing fleets of the Brazilian Amazon were analysed. Data were collected in 893 interviews with boat operators in four major ports on the River Amazon. Boats operating from the largest cities (Belém and Manaus) are mostly operated by hired skippers and non‐permanent crews, while boats from smaller cities (Santarém and Tefé) are mostly owner‐operated and use permanent crews. In the lower Amazon, a large proportion of fishermen (89% in Santarém and 53% in Belém) are based in rural areas, while in the upper Amazon commercial fishermen are predominantly urban‐based. A production function analysis identified boat length, gear type used (gill net/purse seine), number of fishermen employed, quantities of fuel and ice used, and education level of the skipper as significant factors determining the catch. The analysis provided no evidence of regional differences in stock levels. The use of purse seines was associated with significantly higher catches (by 32%), all other factors being equal. Purse seines are banned in the lower Amazon (Santarem and Belem), and this results in overall lower levels of technical efficiency in this region. No significant total scale effect on efficiency was detected. These results are discussed with respect to the institutional sustainability of current fisheries co‐management initiatives.
Variation in thermal tolerance is linked to phosphoglucose isomerase genotype in a montane leaf beetle
Authors: Neargarder G. , Dahlhoff E. P. , Rank N. E.
Published: December 2004

Sierra Nevada populations of the Willow BeetleChrysomela aeneicollis(Schaeffer) experience extreme elevated and subzero temperatures in nature. In these populations, frequencies of phosphoglucose isomerase (PGI) alleles vary with latitude and altitude and respond to climate change. PGI genotypes differ in expression of a stress‐inducible heat shock protein (Hsp70).

Here, differences in tolerance of elevated and subzero extreme temperatures were compared for field‐acclimatized and laboratory‐acclimated larvae and adults possessing three common PGI genotypes (PGI 1–1, 1–4 and 4–4). Three indices of thermal tolerance were measured – CTmax, LT50and Hsp70 expression level.

Thermal tolerance depended on life stage, prior exposure to sublethal stress and PGI genotype. Larvae were generally less tolerant of thermal extremes than adults. For both adults and larvae, prior exposure to sublethal temperatures increased survival after exposure to subsequent stress. Survival after exposure to thermal extremes was consistently related to PGI genotype (1–1 > 1–4 > 4–4), as were expression levels of Hsp70 (1–1 > 1–4 > 4–4).

These results suggest that PGI genotypes differ in tolerance of thermal extremes routinely experienced by beetles in nature. A trade‐off between thermal tolerance and energy allocation may explain the persistence of the PGI polymorphism.
Fate of DNA replication fork encountering a single DNA lesion during oriC plasmid DNA replication in vitro
Authors: Higuchi Kumiko , Katayama Tsutomu , Iwai Shigenori , Hidaka Masumi , Horiuchi Takashi , Maki Hisaji
Published: December 2004

Background: The inhibition of DNA replication fork progression by DNA lesions can lead to cell death or genome instability. However, little is known about how such DNA lesions affect the concurrent synthesis of leading‐ and lagging‐strand DNA catalysed by the protein machinery used in chromosomal replication. Using a system of semi‐bidirectional DNA replication of an oriC plasmid that employs purified replicative enzymes and a replication‐terminating protein of Escherichia coli, we examined the dynamics of the replication fork when it encounters a single abasic DNA lesion on the template DNA.

Results: A DNA lesion located on the lagging strand completely blocked the synthesis of the Okazaki fragment extending toward the lesion site, but did not affect the progression of the replication fork or leading‐strand DNA synthesis. In contrast, a DNA lesion on the leading strand stalled the replication fork in conjunction with strongly inhibiting leading‐strand synthesis. However, about two‐thirds of the replication forks encountering this lesion maintained lagging‐strand synthesis for about 1 kb beyond the lesion site, and the velocity with which the replication fork progressed seemed to be significantly reduced.

Conclusions: The blocking DNA lesion affects DNA replication differently depending on which strand, leading or lagging, contains the lesion.
Cdc42 and Rac small G proteins activated by trans‐interactions of nectins are involved in activation of c‐Jun N‐terminal kinase, but not in association of nectins and cadherin to form adherens junctions, in fibroblasts
Authors: Honda Tomoyuki , Shimizu Kazuya , Kawakatsu Tomomi , Fukuhara Atsunori , Irie Kenji , Nakamura Takeshi , Matsuda Michiyuki , Takai Yoshimi
Published: December 2004

Background: Nectins are Ca2+‐independent immunoglobulin‐like cell‐cell adhesion molecules which associate with cadherins to form adherens junctions (AJs) in epithelial cells and fibroblasts. Nectin‐1 and ‐3 are members of the nectin family which most strongly trans‐interact, causing cell‐cell adhesion. The trans‐interaction between nectin‐1 and ‐3 induces the activation of both Cdc42 and Rac small G proteins in epithelial cells. We studied the roles of Cdc42 and Rac activated in this way in L fibroblasts stably expressing both nectin‐1 and E‐cadherin (nectin‐1‐EL cells).

Results: The trans‐interaction between nectin‐1 and ‐3 induced the activation of Cdc42 and Rac in nectin‐1‐EL cells. Cdc42, and presumably Rac, activated in this way, induced the activation of c‐Jun N‐terminal kinase (JNK), but not p38 mitogen‐activated protein (MAP) kinase or extracellular signal‐regulated kinase (ERK). Cdc42 or Rac was not essential for the association of nectin‐1 and E‐cadherin to form AJs. Reorganization of the actin cytoskeleton was not required for the association of nectin‐1 and E‐cadherin.

Conclusion: These results indicate that Cdc42 and Rac activated by the trans‐interaction of nectins selectively induce the activation of JNK, but are not essential for the association of nectins and cadherin to form AJs in fibroblasts.
GATA‐1 testis activation region is essential for Sertoli cell‐specific expression of GATA‐1 gene in transgenic mouse
Authors: Wakabayashi Junko , Yomogida Kentaro , Nakajima Osamu , Yoh Keigyou , Takahashi Satoru , Engel James Douglas , Ohneda Kinuko , Yamamoto Masayuki
Published: December 2004

Background: The erythroid transcription factor GATA‐1 is also expressed in Sertoli cells of the testis. The testicular expression of GATA‐1 is regulated in a developmental and spermatogenic stage‐specific manner. To further clarify the regulatory mechanisms of testicular GATA‐1 gene expression, we carried out transgenic reporter gene expression analyses.

Results: We found that GATA‐1 expression in Sertoli cells is markedly decreased concomitant with the emergence of elongated spermatids in the seminiferous tubules. Transgenic reporter mouse analyses revealed that a 15 kb GATA‐1 genomic region is sufficient to recapitulate the gene expression profile in Sertoli cells. While the GATA‐1 haematopoietic enhancer and the proximal first exon are included within the 15 kb genomic region, these regulatory elements are not essential for GATA‐1 expression in Sertoli cells. Further analyses using deletion constructs revealed that a 1.5 kb region 5′ to the GATA‐1 haematopoietic enhancer is essential for gene expression in Sertoli cells and this region is referred to as the GATA‐1 testis activation region.

Conclusion: These results thus demonstrated that the GATA‐1 testis activation region is essential for Sertoli cell‐specific expression of GATA‐1 gene. The 15 kb genomic region is applicable and useful for the expression vector system specific for adult Sertoli cells in stage VII to IX.
Response of terrestrial carbon uptake to climate interannual variability in China
Authors: CAO MINGKUI , PRINCE STEPHEN D. , LI KERANG , TAO BO , SMALL JENNIFER , SHAO XUEMEI
Published: December 2004

The interest in national terrestrial ecosystem carbon budgets has been increasing because the Kyoto Protocol has included some terrestrial carbon sinks in a legally binding framework for controlling greenhouse gases emissions. Accurate quantification of the terrestrial carbon sink must account the interannual variations associated with climate variability and change. This study used a process‐based biogeochemical model and a remote sensing‐based production efficiency model to estimate the variations in net primary production (NPP), soil heterotrophic respiration (HR), and net ecosystem production (NEP) caused by climate variability and atmospheric CO2 increases in China during the period 1981–2000. The results show that China's terrestrial NPP varied between 2.86 and 3.37 Gt C yr−1 with a growth rate of 0.32% year−1 and HR varied between 2.89 and 3.21 Gt C yr−1 with a growth rate of 0.40% year−1 in the period 1981–1998. Whereas the increases in HR were related mainly to warming, the increases in NPP were attributed to increases in precipitation and atmospheric CO2. Net ecosystem production (NEP) varied between −0.32 and 0.25 Gt C yr−1 with a mean value of 0.07 Gt C yr−1, leading to carbon accumulation of 0.79 Gt in vegetation and 0.43 Gt in soils during the period. To the interannual variations in NEP changes in NPP contributed more than HR in arid northern China but less in moist southern China. NEP had no a statistically significant trend, but the mean annual NEP for the 1990s was lower than for the 1980s as the increases in NEP in southern China were offset by the decreases in northern China. These estimates indicate that China's terrestrial ecosystems were taking up carbon but the capacity was undermined by the ongoing climate change. The estimated NEP related to climate variation and atmospheric CO2 increases may account for from 40 to 80% to the total terrestrial carbon sink in China.
The catchment and climate regulation of pCO2 in boreal lakes
Authors: SOBEK SEBASTIAN , ALGESTEN GRETE , BERGSTRÖM ANN‐KRISTIN , JANSSON MATS , TRANVIK LARS J.
Published: December 2004

The regulation of surface water pCO2 was studied in a set of 33 unproductive boreal lakes of different humic content, situated along a latitudinal gradient (57°N to 64°N) in Sweden. The lakes were sampled four times during one year, and analyzed on a wide variety of water chemistry parameters. With only one exception, all lakes were supersaturated with CO2 with respect to the atmosphere at all sampling occasions. pCO2 was closely related to the DOC concentration in lakes, which in turn was mainly regulated by catchment characteristics. This pattern was similar along the latitudinal gradient and at different seasons of the year, indicating that it is valid for a variety of climatic conditions within the boreal forest zone. We suggest that landscape characteristics determine the accumulation and subsequent supply of allochthonous organic matter from boreal catchments to lakes, which in turn results in boreal lakes becoming net sources of atmospheric CO2.
Effects of elevated CO2 on the size structure in even‐aged monospecific stands of Chenopodium album
Authors: NAGASHIMA HISAE , YAMANO TAKASHI , HIKOSAKA KOUKI , HIROSE TADAKI
Published: December 2004

To investigate the effect of elevated CO2 on the size inequality and size structure, even‐aged monospecific stands of an annual, Chenopodium album, were established at ambient and doubled CO2 with high and low nutrient availabilities in open top chambers. The growth of individual plants was monitored non‐destructively every week until flowering. Elevated CO2 significantly enhanced plant growth at high nutrients, but did not at low nutrients. The size inequality expressed as the coefficient of variation tended to increase at elevated CO2. Size structure of the stands was analyzed by the cumulative frequency distribution of plant size. At early stages of plant growth, CO2 elevation benefited all individuals and shifted the whole size distribution of the stand to large size classes. At later stages, dominant individuals were still larger at elevated than at ambient CO2, but the difference in small subordinate individuals between two CO2 levels became smaller. Although these tendencies were found at both nutrient availabilities, difference in size distribution between CO2 levels was larger at high nutrients. The CO2 elevation did not significantly enhance the growth rate as a function of plant size except for the high nutrient stand at the earliest stage, indicating that the higher biomass at elevated CO2 at later stages in the high nutrient stand was caused by the larger size of individuals at the earliest stage. Thus the effect of elevated CO2 on stand structure and size inequality strongly depended on the growth stage and nutrient availabilities.
Climatic trends and advancing spring flight of butterflies in lowland California
Authors: FORISTER MATTHEW L. , SHAPIRO ARTHUR M.
Published: December 2004

Many studies, largely from cool‐temperate latitudes, have investigated the relationship between the timing of biological events and changes in climatic conditions during the past few decades. Relatively little is known about the response of plants and animals at lower latitudes. Here we show that the average first spring flight of 23 butterfly species in the Central Valley of California has advanced to an earlier date over the past 31 years. Among the species that have appeared significantly earlier, the average shift is 24 days. Climatic conditions (largely winter temperature and precipitation) are found to explain a large part of the variation in changing date of first flight. These results suggest a strong ecological influence of changing climatic conditions on a suite of animals from a mid‐latitude, Mediterranean climate.
Locating eutrophication effects across British vegetation between 1990 and 1998
Authors: Smart Simon M. , Robertson Joanne C. , Shield Eleanor J. , Van De Poll Helena M.
Published: December 2004

Large‐scale ecological surveillance data were analysed to determine the locations of apparent eutrophication effects across common British vegetation types between 1990 and 1998. Plant species composition was recorded from a total of 9514 fixed plots located in a stratified, random sample of 501 1 km squares across Britain. Changes in plant species composition along a gradient of substrate fertility were inferred from statistical tests of change in mean Ellenberg fertility value calculated for each fixed plot. Plots were grouped by eight vegetation types, five landscape features (hedges, road verges, watercourse banks, small biotopes, larger units in fields and unenclosed land) and six environmental zones. Tests of change in mean Ellenberg value were carried out on all combinations of these strata. Decision tree modelling was used to identify groups of test outcomes sharing the same direction of change and where each group was defined by a minimum number of strata. Post hoc power analysis was used to select statistically non‐significant test outcomes that could be used to infer stability in the sampled sub‐population.

Out of a total of 142 tests of change in fertility value, 67% were increases, 8% were reductions and 25% indicated stability. The best overall predictor of increases in fertility value, and therefore of shifts in favour of plants suited to higher substrate fertility, was vegetation type. Irrespective of landscape feature and environmental zone, increased means were associated with infertile grasslands, moorland, upland woodlands and heath/bog. Already highly fertile grasslands and woodland assemblages in lowland Britain remained largely stable. The small number of decreasing test outcomes were associated with arable land in Scotland, Wales and western England. These patterns of change are hypothesized to reflect pervasive land‐use drivers combined with the inherent responsiveness of the vegetation.
A simulation model of a dairy forage system to evaluate feeding management strategies with spring rotational grazing
Authors: Coléno F. C. , Duru M. , Soler L. G.
Published: December 2004

Abstract To counteract a decrease in the availability of grazing for feeding dairy cows in France, a simulation model is proposed in the paper, which combines decision and agronomic submodels to study forage system management strategies compatible with spring grazing use. Nine strategies were tested with the model using a sequence of 16 climatic years. Three of these strategies come from a survey in south‐west France and six others were designed with research scientists or farm advisors. The strategies differ in the duration of maize silage feeding, the area dedicated to maize silage and the area dedicated to grass silage. Results from simulation models show that the consequence of a large and constant maize silage area is a high maize silage overstock if there is an early turnout or a high grass silage overstock if turnout is late. The consequence of a low maize area is a high grazing duration combined in some years with feeding shortages. Strategies that have no feeding shortage and a low level of maize and grass silage overstock have a high grazing duration and have no constant maize or grass silage areas. The solution proposed to avoid climatic risk, and its consequences on feeding, is based on two procedures: use of reserve areas for production and allowing the production programme to be modified to take into account fresh information, especially weather records.
Factor IX inhibition and epitope localization of factor IX inhibitor antibodies in haemophilia B patients with anaphylactoid reactions
Authors: YAMAMOTO M. , KAMISUE S. , SAWAMOTO Y. , NAKAI H. , TANAKA I. , SHIMA M. , TAKAMATSU J. , OGUNI T. , KINOSHITA S. , GIDDINGS J. C. , YOSHIOKA A.
Published: December 2004

Summary. We describe the results of immunological studies, reaction kinetics and epitope localization of six inhibitor antibodies to factor IX (FIX) developed in severe haemophilia B patients. Three of the six patients had suffered recent anaphylactoid reactions to FIX concentrates, two others had in the past and one had none. All six inhibitors rapidly inactivated FIX activity in vitro, and the prominent immunoglobulin (IgG) subclass of the antibody was IgG4 when analysed with ELISA. Interestingly, we found an additional IgG1 component in the antibody samples from the patients who had recently experienced anaphylactoid reactions to FIX. When analysed with Western blotting in these three patients, the IgG4 antibody bound with enhanced affinity to the heavy chain or the light chain of FIX, and in two of the three the IgG1 antibody also bound strongly to the FIX heavy chain. The results suggest that the heavy chain of FIX might play a more significant role than the light chain in the pathogenesis of anaphylactoid reactions in haemophilia B patients with FIX inhibitors.
Absence of intrafamilial transmission of hepatitis C in patients with inherited bleeding disorders
Authors: DASANI H. , JACKSON H. , JONES J. A. , HOWLETT J.
Published: December 2004

Summary. Hepatitis ‘C’ virus (HCV) infection has caused significant anxiety in patients with inherited bleeding disorders. A significant number of patients with HCV have developed chronic liver disease, cirrhosis and hepatocellular carcinoma. The exact risk of heterosexual and contact transmission is unclear at the moment. A test for antibody to hepatitis ‘C’ was offered, after counselling, to spouses and family members of 118 known hepatitis ‘C’ antibody positive patients with inherited bleeding disorders. Two hundred and fifteen family members were tested, 73 partners and 142 household contacts; all were found negative for hepatitis ‘C’. Our experience confirms the low risk of heterosexual and contact transmission of hepatitis ‘C’ virus.
Fatal liver failure in haemophiliacs with HIV‐induced immunodeficiency: observation of six patients
Authors: TOYODA H. , FUKUDA Y. , NAKANO I. , KATANO Y. , TAKAMATSU J. , SAITO H. , HAYAKAWA T.
Published: December 2004

We observed six cases of haemophiliacs with HIV‐induced immunodeficiency who died from fatal liver failure despite the absence of evident cirrhosis. They all had the infection with hepatitis viruses (two patients with hepatitis B and D viruses and four patients with hepatitis C virus) and their CD4 counts were severely decreased. They were much younger than cirrhotic haemophiliacs without HIV. Their serum levels of hyaluronic acid and type IV collagen were lower than those in haemophiliacs with cirrhosis, and were normal. No patients had experienced symptoms or concomitant diseases characteristic of cirrhosis, such as ascites, jaundice, oesophageal/gastric varices or hepatocellular carcinoma, except for one case who had a history of mild ascites. The characteristics of this liver failure were different from liver failure resulting from cirrhosis caused by chronic hepatitis, which suggests liver failure that is specific to patients with immunodeficiency. This kind of liver failure can be a factor threatening survival in patients with HIV infection and with hepatitis virus co‐infection in an immunodeficient state.
The overall effectiveness of prophylaxis in severe haemophilia
Authors: Panicker J. , Warrier I. , Thomas R. , Lusher J. M.
Published: December 2004

Summary.  The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on‐demand treatment of haemophilic patients. Twenty‐five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one–six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg−1 (20–30 U kg−1) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg−1 recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long‐term morbidity and a better quality of life despite increased central lines and higher factor usage.
Treatment of haemophilia in the developing countries
Authors: Chuansumrit A.
Published: December 2004

Summary. In developing countries, most of the patients with haemophilia are in the paediatric age group as they seldom reach adulthood because of inadequate treatment. Haemophilia is not given the priority it deserves as there are high numbers of other serious health problem. Haemophilia care should be integrated into the existing healthcare system of a primary care centre, a treatment centre, a comprehensive care centre and a reference centre. It is considered important to educate the personnel through the curriculum of medical students and all healthcare personnel. Diagnosis should be started at the antenatal stage and subsequently confirmed by laboratory testings. Qualified therapeutic products should be produced locally in combination with imported affordable factor concentrate. In‐house preparation of fibrin glue is helpful for dental procedures without the need for any blood component. Home care treatment is essential and can be adopted even by parents with low literacy. Lastly, research for laboratory diagnosis, treatment and prevention should be continuously conducted to serve people with haemophilia specifically in developing countries.
Long‐term FEIBA prophylaxis does not prevent progression of existing joint disease
Authors: Hilgartner M. W. , Makipernaa A. , Dimichele D. M.
Published: December 2004

Summary.  Activated prothrombin complex concentrates have been used to treat bleeding episodes for patients who have developed an inhibitor to factor VIII (FVIII). FEIBA‐Vh® (FVIII bypassing activity, FEIBA) has been used since 1970 for this purpose and with FVIII for immune tolerance programmes. Studies have not been presented to show the safety and efficacy of FEIBA when given over a long period of time to prevent haemophilic arthropathy with bleeding into the joints of these patients. This study was undertaken to ascertain the outcome of haemophilic arthropathy with FEIBA prophylaxis. Data were collected on seven patients with known long‐standing high‐titre FVIII inhibitors given FEIBA prophylaxis for 3–6½ years. Patients were given 50–100 units of FEIBA three to four times weekly. A functional joint evaluation revealed some degree of arthropathy already present in all patients at time of prophylaxis initiation. Safety was measured by medical status, evidence of thrombosis, life‐threatening bleeding and inhibitor titre. Efficacy was measured for joint outcome by a functional physical therapeutic scale. At the conclusion of the study, efficacy was mixed as all of the joints for which the patients were placed on prophylaxis had progressed and developed synovitis. Two patients had a functional improvement in their arthropathy, and all were functional enough to attend regular school. The product was deemed safe for long‐term use, as there were no complications of therapy with no thrombosis, no life‐threatening bleeding episodes and no anamnesis caused by FEIBA alone. Inhibitor titres fell in all patients over the course of the study. Total product usage ranged from approximately 9373–15 571 U kg−1 year−1. FEIBA is safe for long‐term prophylaxis when given in the recommended dosage for an extended period of time. Efficacy to prevent arthropathy could not be seen as all patients had some degree of arthropathy at time of prophylaxis initiation. An additional study needs to be performed using FEIBA before arthropathy has developed.
Central venous access devices in haemophilia
Authors: Valentino L. A. , Ewenstein B. , Navickis R. J. , Wilkes M. M.
Published: December 2004

Summary.  Central venous access devices (CVADs) can facilitate repeated and/or urgent administration of coagulation factors in haemophilic patients. We conducted a systematic review and meta‐analysis of complication rates and risk factors for poor outcome. Forty‐eight studies with a total of 2704 patients and 2973 CVADs were included. The primary indications for CVADs were immune tolerance therapy (34.9% of patients), difficult venous access (31.8%) and prophylaxis (29.1%). Fully implanted CVADs were employed in 77.4% of cases and external CVADs in 22.6%. A total of 1190 infections were reported, and the pooled incidence of infection was 0.66 per 1000 CVAD days [confidence interval (CI), 0.44–0.97 per 1000 CVAD days]. Among patients developing infection, the pooled time to first infection was 295 days (CI, 181–479 days). Presence of inhibitors was an independent risk factor for infection with an incidence rate ratio (IRR) of 1.67 (CI, 1.15–2.43). Infection was less likely in patients >6 years of age (IRR, 0.46; CI, 0.27–0.79) and recipients of fully implanted CVADs (IRR, 0.31; CI, 0.12–0.86). Available information on thrombosis was limited, with only 55 cases being reported. Eventually, 31.3% of CVADs were removed, and infection was the reason for removal in 69.9% of cases and thrombosis in 4.1%. The pooled time period CVADs remained indwelling prior to removal or the expiration of the study observation period was 578 days per CVAD (CI, 456–733 days per CVAD). CVADs can confer major benefits in patients with haemophilia requiring long‐term venous access, and serious complications are rare.
Comparing outcomes of different treatment regimens for severe haemophilia
Authors: Van Den Berg H. M. , Fischer K. , Van Der Bom J. G.
Published: December 2004

Summary.  Published retrospective reports from France, the Netherlands and Sweden were analysed for data relating to the long‐term outcomes (primarily the development of arthropathy) of three regimens for the management of severe haemophilia: on‐demand treatment, intermediate‐dose prophylaxis and high‐dose prophylaxis. The mean annual consumption of factor concentrate was also compared. These data indicate that both prophylaxis regimens resulted in significantly improved long‐term outcomes, as assessed by pain, clinical and radiological assessment scores. At the same time, the most recently reported annual factor consumption levels of these young adult patients are comparable in the on‐demand and intermediate‐dose prophylaxis cohorts, suggesting that the improvement in long‐term clinical outcomes and reduced risk of arthropathy may lead to reduced factor consumption in adult patients who received early prophylactic therapy.
A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres
Authors: Blanchette V. S. , Mccready M. , Achonu C. , Abdolell M. , Rivard G. , Manco‐Johnson M. J.
Published: December 2004

Summary.  A survey was conducted in 2002 to determine the pattern of factor prophylaxis use in boys ≤18 years of age with haemophilia followed in North American treatment centres. Responses were obtained from 4553 cases (74% haemophilia A, 26% haemophilia B). The frequency of prophylaxis, defined as factor infusion greater than or equal to once per week for ≥45 weeks per year, was significantly higher for haemophilia A vs. haemophilia B cases (51% vs. 32%, P< 0.0001), and for boys with severe haemophilia A living in Canada vs. the USA (77% vs. 47%, P< 0.0001). Use of full‐dose prophylaxis, defined as the infusion of 25–40 IU kg−1 of factor VIII on alternate days (minimum three times per week) or 25–40 IU kg−1 of factor IX twice weekly, was similar for boys ≤5 years of age in both Canada and the USA (30% and 33% haemophilia A and 35% and 13% haemophilia B). Reasons for initiating prophylaxis included a history of joint bleeding (88%) and age ≤2 years (23%). For prophylaxis triggered by joint bleeding, 38% of haemophilia treatment centres indicated that they would initiate prophylaxis after the first joint bleed and 66% after a history of target joint bleeding, defined most frequently as 2–4 bleeds over a 3–6 consecutive month period. A central venous line was used to ensure easy venous access for full‐dose prophylaxis therapy in 80% of boys ≤5 years of age. These data offer a basis for projecting long‐term factor concentrate needs for persons with haemophilia living in North America.
North American prophylaxis studies for persons with severe haemophilia: background, rationale and design
Authors: Manco‐Johnson M. J. , Blanchette V. S.
Published: December 2004

Summary.  Arthropathy is associated with the greatest cost and morbidity to persons with haemophilia. Clinical protocols have been developed empirically to prevent or retard the development of joint disease using routine infusions of replacement factor concentrate. However, randomized clinical trials to determine optimal therapy to prevent joint disease in persons with severe haemophilia are lacking. Two clinical trials are ongoing to answer important clinical questions about the prevention of arthropathy. The first, a US randomized clinical trial, is comparing an aggressive multiple‐infusion episode‐based protocol to standard alternate‐day prophylaxis to determine whether prevention of joint disease requires prevention of the bleeding event, per se, or can be achieved by promoting complete resolution of each bleeding event in the joint. This study included the development and validation of sensitive new physical and imaging scales to detect the earliest signs of joint disease in young children. The second, a single‐arm, open‐label Canadian study, is asking whether prevention of joint disease in young children can be individualized by escalating the dose and frequency of routine replacement infusions of factor concentrate based upon the clinical course of haemophilia in the affected child. Both of these studies will contribute valuable information regarding optimal therapy and will help establish evidence‐based medicine for the management of severe haemophilia.
Consensus perspectives on prophylactic therapy for haemophilia: summary statement
Authors: Berntorp E. , Astermark J. , Björkman S. , Blanchette V. S. , Fischer K. , Giangrande P. L. F. , Gringeri A. , Ljung R. C. , Manco‐Johnson M. J. , Morfini M. , Kilcoyne R. F. , Petrini P. , Rodriguez‐Merchan E. C. , Schramm W. , Shapiro A. , M. Van Den Berg H. , Hart C.
Published: December 2004

Summary.  Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long‐term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality‐of‐life assessment instruments, and cost‐benefit analyses.
Purification, isolation and search for possible functions of a phase‐related 6080‐Da peptide from the haemolymph of the desert locust, Schistocerca gregaria
Authors: Rahman Mazibur M. , Baggerman Geert , Begum Murshida , De Loof Arnold , Breuer Michael
Published: December 2004

Abstract. A novel 6‐kDa peptide has been isolated from the haemolymph of the desert locust, Schistocerca gregaria (Forskal) (Orthoptera: Acrididae), and fully identified. Its concentration is higher in crowd‐reared (gregarious) animals than in isolated‐reared (solitarious) ones. Its concentration decreases progressively from generation to generation with solitarization of gregarious locusts. The peptide is also present in freshly laid eggs. The concentration in eggs is higher in those from crowd‐reared locusts. It is likely that the peptide is transferred from the female's haemolymph into the eggs because injection of the peptide into females before oviposition increases the amount of the 6‐kDa peptide in the eggs. A two‐step HPLC purification procedure for this peptide is described. It allowed several bioassays to test for a possible function. Although the peptide's concentration in the haemolymph is high (0.1 mm), which suggests some physiological function, we have as yet not been able to identify a function. We hypothesize that the 6‐kDa peptide may somehow play a role as a maternal factor in the determination of the phase‐state of the offspring.
Nonparametric Estimation of the Sojourn Time Distributions for a Multipath Model
Authors: Wang Weijing
Published: December 2004

We use a multipath (multistate) model to describe data with multiple end points. Statistical inference based on the intermediate end point is challenging because of the problems of nonidentifiability and dependent censoring. We study nonparametric estimation for the path probability and the sojourn time distributions between the states. The methodology proposed can be applied to analyse cure models which account for the competing risk of death. Asymptotic properties of the estimators proposed are derived. Simulation shows that the methods proposed have good finite sample performance. The methodology is applied to two data sets.
Hazard-Based Nonparametric Survivor Function Estimation
Authors: Prentice Ross L. , Zoe Moodie F. , Wu Jianrong
Published: December 2004

A representation is developed that expresses the bivariate survivor function as a function of the hazard function for truncated failure time variables. This leads to a class of nonparametric survivor function estimators that avoid negative mass. The transformation from hazard function to survivor function is weakly continuous and compact differentiable, so that such properties as strong consistency, weak convergence to a Gaussian process and bootstrap applicability for a hazard function estimator are inherited by the corresponding survivor function estimator. The set of point mass assignments for a survivor function estimator is readily obtained by using a simple matrix calculation on the set of hazard rate estimators. Special cases arise from a simple empirical hazard rate estimator, and from an empirical hazard rate estimator following the redistribution of singly censored observations within strips. The latter is shown to equal van der Laan's repaired nonparametric maximum likelihood estimator, for which a Greenwood-like variance estimator is given. Simulation studies are presented to compare the moderate sample performance of various nonparametric survivor function estimators.
Chromosome number and microsporogenesis in a pentaploid accession of Brachiaria brizantha (Gramineae)
Authors: Risso‐Pascotto C. , Pagliarini M. S. , Borges do Valle C. , Mendes‐Bonato A. B.
Published: December 2004

Chromosome number, microsporogenesis and mode of reproduction are described for an accession of Brachiaria brizantha, a grass of African origin. Cytological analysis revealed that the accession BRA005886 is pentaploid (2n = 5x = 45), with a base number of x = 9. Multivalent chromosome associations, from tri‐ to pentavalents, were recorded in diakinesis, and the further meiotic behaviour was highly irregular as well. Most abnormalities were related to irregular chromosome segregation commonly found in polyploids. Micronuclei were observed following telophases I and II. Some micronuclei near the cell wall were released as microcytes, whereas others remained in the tetrad. Other meiotic abnormalities, such as cell fusion and the absence of cytokinesis causing the formation of dyads and triads were also recorded. Binucleate microspores and 2n microspores resulting from nucleus restitution were observed among the normal ones. Limitations of this accession for use in hybridization programmes are discussed.
Cyclic AMP Signalling During Mammalian Sperm Capacitation – Still Largely Terra Incognita
Authors: Harrison RAP
Published: December 2004

Contents

Cyclic AMP is known to play a major role in intracellular signalling during mammalian sperm capacitation. However, despite much research, many of the molecular details of cyclic AMP's involvement remain obscure. In this review, I discuss the following aspects, presenting some original data as illustration where relevant. With respect to cyclic AMP synthesis, uncertainties exist as to the number of forms of adenylyl cyclase that are present in the spermatozoon, whether they are cytosolic or bound to subcellular structures, and which physiological effectors they respond to (e.g. bicarbonate, Ca2+, or receptor‐coupled G‐proteins). While net intracellular levels of cyclic AMP in spermatozoa depend upon the relative activities of adenylyl cyclase and phosphodiesterase, there are wide between‐sample variations within species, both in basal levels and in levels attained after activation of the cyclase (e.g. after sperm treatment with bicarbonate). Moreover, minor changes in bulk cyclic AMP levels can result in large changes in cyclic AMP‐dependent functions. Finally, while cyclic AMP levels respond very rapidly to sperm treatment by effectors such as bicarbonate and Ca2+ (key components of capacitating media), there are big discrepancies between the rates of functional response. For example, enhancement of motility and collapse of phospholipid asymmetry take place within a few minutes, whereas more than 1 h of exposure to capacitating conditions is needed for cyclic AMP‐dependent protein tyrosine phosphorylation to become detectable or for the sperm population to attain a capacitated state.
Genetic alterations of human brain tumors as molecular prognostic factors
Authors: Shiraishi Tetsuya , Tabuchi Kazuo
Published: December 2004

Despite a number of basic and clinical studies, it is still very difficult to improve the prognosis of patients with high‐grade astrocytoma. However, the recent success of procarbazine, N‐(2‐chloroethyl)‐N"‐cyclohexyl‐N‐nitrosourea and vincristine (PCV) chemotherapy for oligodendrogliomas that have lost chromosomes 1p and 19q has encouraged the authors to evaluate the biological behavior of brain tumors by means of genetic analysis. Both the disorders of the p53/MDM2/p14ARF and the p16INK4a/RB signaling pathways have been found to play an essential role in tumorigenesis of various brain tumors. Herein, the authors summarize the genetic alterations of brain tumors by mainly focusing on two pathways that appear to affect significantly the patient prognosis.
Checkpoints and pitfalls in the experimental neuropathology of circulatory disturbance
Authors: Kuroiwa Toshihiko , Okeda Riki
Published: December 2004

In neural tissue injury many pathological processes are common to different neurological disorders, including cerebral ischemia. Because ischemia has a fundamentally simple impact on neural tissue, good laboratory modeling can help improve the general understanding of the neuropathological processes involved. Summarized here are some basic principles that should be followed to ensure that cerebral ischemia studies are reproducible and informative: (i) selection of an appropriate model of cerebral ischemia in an appropriate species (although rodents are widely used for genomic studies, the use of larger animals, with brain structures macroscopically similar to those of humans, is appropriate for many studies, e.g. of white matter lesions or the pathophysiology of cerebral edema); (ii) correct maintenance of physiological parameters, including body temperature, systemic blood pressure, and blood gas tensions, under appropriate general anesthesia; (iii) selection of an appropriate method of cerebral blood flow (CBF) monitoring (decisions include whether or not the experiment requires real‐time monitoring, in vivo measurement, and CBF mapping); (iv) appropriate timing of drug application in therapeutic studies (many drugs that are effective when given immediately after a short period of ischemia are ineffective in clinical trials, probably because of longer periods of ischemia and delayed drug delivery in clinical settings); and (v) multiparametric evaluation of therapeutic effect (with the recent increase in diagnosis of cases of mild stroke, measurement of mortality and infarct size have proven to be insufficient for the evaluation of therapeutic effect). Use of mild ischemia models and batteries of neurological tests for individual neurological functions, such as motor, somatosensory, and visual function, are becoming important in experimental ischemia research. In histological evaluation, assessment of the extent of both selective neuronal loss and the infarct will become mandatory. Regional analysis of each brain structure and coordination of the results with the apparent neurological dysfunction is a promising approach.
A case of completely resolved pneumatocoeles in desquamative interstitial pneumonia
Authors: KIM Kyu‐Sik , KIM Young‐Chul , PARK Kyung‐Ok , LIM Sung‐Chul , KIM Yun‐Hyeon , NA Kook‐Joo , KIM Kyung‐Soo
Published: December 2004

Abstract:  Desquamative interstitial pneumonia (DIP), also known as alveolar macrophage pneumonia (AMP), represents a subset of idiopathic interstitial pneumonia that responds better to steroids and has a more favourable prognosis than usual interstitial pneumonia. Recently, we encountered a case of DIP with the formation of multiple pulmonary cysts during corticosteroid maintenance treatment. After the introduction of cyclophosphamide, the cysts gradually disappeared. This complete resolution is believed to have resulted from the clearance of check‐valve‐like bronchiolar obstructions that may be another interesting terminal airway pathology in DIP.