bluuebunny/crossref_metadata_2025 huggingface dataset:
Women and von Willebrand disease
Authors: Lee C.A.
Published: March 2003

In 1926 von Willebrand made the observation that ‘the trait seemed especially to be seen among women’. A pictorial bleeding assessment chart (PBAC) defines menorrhagia with a score of >100 representing >80 ml blood loss. A retrospective study has shown menorrhagia in 74% patients with von Willebrand disease (vWD) and vWD in 13% patients with menorrhagia. Although von Willebrand factor (vWF) increases in pregnancy, there may be an increased incidence of post partum haemorrhage. DDAVP is a useful treatment for menorrhagia and postnatally. Clotting factor concentrates containing vWF may be required.
Drug‐induced and traumatic nail problems in the haemophilias
Authors: Heim M. , Schapiro J. , Wershavski M. , Martinowitz U.
Published: March 2003

Many persons with haemophilia suffer from HIV and receive highly active antiretroviral therapy. Three patients received indinavir and required surgery due to ingrown toenails. Two patients suffered from a traumatic subungual haematoma. The treatment protocol is described whereby the pressure exerted onto the germinal layer and the nail bed is relieved in order to alleviate pain and nail matrix damage.
Participation in sports by Dutch persons with haemophilia
Authors: Heijnen  , Mauser‐Bunschoten  , Roosendaal
Published: March 2003

Patients with haemophilia are now widely advised to participate in sports. However, no extensive data are available about their actual participation. A self‐administered questionnaire was used to investigate sports participation by persons with haemophilia in the Netherlands. All 293 questionnaires that were distributed have been returned; 217 were from people with severe haemophilia A or B (this is 40% of the severely affected Dutch population with haemophilia). Of this group, 155 (71%) participate in one or more sports: 66 swim, 36 cycle, 21 play tennis, 18 do fitness exercises, 16 ice skate, 10 ski and 10 play table tennis; in total 44 different sports are mentioned. Of a group of 16 persons with haemophilia who are unable to run, 10 (63%) participate in sport and of a group of 91 who can only run sometimes, 64 (70%) engage in sports. This shows that there are ample opportunities for persons with haemophilia to participate in sports, even if they are unable to run. Severely affected persons with haemophilia are as active as the general Dutch population; in fact, a higher proportion swims and/or cycles. In conclusion, sports participation in the Netherlands by persons with haemophilia is in accordance with World Federation of Hemophilia directives.
Continuous infusion of recombinant activated factor VII during caesarean section delivery in a patient with congenital factor VII deficiency
Authors: Jiménez‐Yuste  , Villar  , Morado  , Canales  , Hernández  , Sanjurjo  , Quintana  , Hernández‐Navarro
Published: March 2003

Recombinant activated factor VII (rFVIIa) can be used as an alternative therapy in patients with FVII deficiency. However, as the drug has a very short half‐life, continuous infusion could be a meaningful administration modality. We report the case of a 30‐year‐old woman with moderate FVII deficiency and human immunodeficiency virus infection who underwent a caesarean section delivery. She was treated with a continuous infusion of rFVIIa and did not suffer any bleeding complication. The continuous infusion of rFVIIa was a safe and effective therapeutic approach for our patient, maintaining her levels of FVII:C and avoiding bleeding during caesarean section and afterwards.
Poor response to interferon treatment for chronic hepatitis C in human immunodeficiency virus‐infected haemophiliacs
Authors: Hayashi K. , Fukuda Y. , Nakano I. , Katano Y. , Yokozaki S. , Toyoda H. , Takamatsu J. , Hayakawa T.
Published: March 2003

We performed a pilot study to evaluate the factors associated with response to interferon (IFN) therapy for chronic hepatitis C (CHC) with human immunodeficiency virus (HIV) coinfected haemophiliacs. Seven haemophiliacs, coinfected with HIV and hepatitis C virus (HCV), received 9 mega‐units (MU) of natural IFN‐alpha daily during the first 2 weeks and then three times a week for 22 weeks, all injected subcutaneously. Six patients were receiving zidovudine (AZT) 600 mg day−1 and didanosine (ddI) 200 mg day−1 during IFN therapy. This treatment was safe and well tolerated. Four patients had no detectable serum HCV‐RNA at the end of therapy, but long‐term, none of the seven patients achieved a sustained response, i.e. undetectable serum HCV‐RNA with persistently normal serum alanine aminotransferase (ALT) 6 months after therapy. IFN did not affect CD4‐positive cell counts. Most of our patients had high HCV‐RNA loads and/or low CD4 counts, both unfavourable markers for IFN therapy. In conclusion, IFN therapy did not eradicate HCV from haemophiliacs coinfected with HIV.
Post‐synoviorthesis rehabilitation in haemophilia
Authors: Querol F. , Rodriguez‐Merchan E.C. , Aznar J.A. , Lopez‐Cabarcos C. , Villar A.
Published: March 2003

The efficacy of radiosynoviorthesis in the management of chronic haemophilic synovitis has been proven. Like replacement therapy, however, this procedure has no effect on muscle strength or endurance, range of movement, coordination, or the patient’s physical condition in general. All the factors just enumerated are essential for the recovery and maintenance of the haemophiliac’s quality of life. That is why rehabilitation and physiotherapy are so important, since no medical therapy or surgical procedure are by themselves capable of preventing disabilities.
The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development
Authors: Astermark J. , Berntorp E. , White G. C. , Kroner B. L. ,   THE MIBS STUDY GROUP
Published: March 2003

The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty‐five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high‐ or low‐responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35–62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11–21%) corresponding to a relative risk of 3.2 (95% CI 2.1–4.9). Immune‐tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.
Dental health indices and caries‐related microflora in children with severe haemophilia
Authors: Sonbol H. , Pelargidou M. , Lucas V. S. , Gelbier M. J. , Mason C. , Roberts G. J.
Published: March 2003

The purpose of this work was to investigate the prevalence of dental caries, bacterial dental plaque, gingivitis, enamel defects and caries‐ related microflora in children with severe haemophilia. Thirty‐eight children with severe haemophilia (factor VIII and IX < 2 U dL–1) were recruited from Great Ormond Street Hospital for Children and matched for age, gender and ethnicity with healthy control children from the Eastman Dental Institute. Indices were recorded for decayed, missing, and filled teeth and surfaces in both the deciduous dentition (dmfs/dmft) and the permanent dentition (DMFS/DMFT). The plaque and gingivitis scores and developmental enamel defects were also recorded. The caries‐related microflora was sampled and cultured for Streptococcus mutans, and Lactobacilli and Candida species. A significantly greater proportion of children with severe haemophilia were caries‐free compared with the controls (36.7% vs. 13.3%; P=0.04). Both the DMFS and DMFT were significantly greater in the controls (3.6 and 2.8, respectively) compared with the haemophilia group, (0.8 and 0.7; P=0.007 and P=0.04). The plaque score for the permanent dentition only was significantly greater for the control children (24.2) compared with the haemophilia group, (10.2; P=0.04). The mean number of colony forming units of S. mutans was significantly greater in the control group compared with the haemophilia group (P=0.05). We conclude that children with severe haemophilia have a significantly lower prevalence of dental caries compared with matched, healthy controls.
Bacterial endocarditis in a child with haemophilia B: risks of central venous catheters
Authors: Hothi D. K. , Kelsall W. , Baglin T. , Williams D. M.
Published: March 2003

The use of central venous catheters may be complicated by thrombosis and infection. We report a case of a needle‐phobic 5‐year‐old boy with factor IX deficiency, in whom a portacath was inserted owing to poor compliance with prophylactic treatment. Within a week, he developed a Staphylococcus aureus line infection that was treated with a 2‐week course of intravenous antibiotics. One month later he presented with nonspecific symptoms and blood cultures again grew S. aureus. An echocardiogram revealed a large vegetation adherent to the tricuspid valve, confirming the diagnosis of bacterial endocarditis. His clinical course was further complicated by the development of pulmonary emboli. Medical treatment with intravenous antibiotics led to a successful resolution of the endocarditis and pulmonary emboli with a favourable long‐term outcome.
The haemophilic pseudotumour
Authors: RODRIGUEZ‐MERCHAN E. C.
Published: March 2003

The management of the patient with a haemophilic pseudotumour is complex and carries a high rate of potential complications. There are a number of therapeutic alternatives for this dangerous condition: embolization, radiation, percutaneous management, surgical removal and exeresis, and filling of the dead cavity. It is hoped that with the advent of widespread maintenance therapy, pseudotumours will be less common in the future. It is important that they are diagnosed early, and prevention of muscular haematomas is key to reducing their incidence. Untreated, proximal pseudotumours will ultimately destroy soft tissues, erode bone and may produce neurovascular complications. Surgical excision is the treatment of choice but should only be carried out in major haemophilia centres by a multidisciplinary surgical team.
Total knee arthroplasty in HIV‐positive haemophilic patients
Authors: RODRIGUEZ‐MERCHAN E. C. , WIEDEL J. D.
Published: March 2003

In the era of total joint replacements in orthopaedics, total knee arthroplasty (TKA) should be indicated in haemophilic patients suffering from severe knee pain and disability. However, the expected high risk of infection and other postoperative complications is a concern. Although the message of this article may seem conservative, it should not be inferred that TKA should still be avoided in a haemophilic patient, but rather that the orthopaedic surgeon should weigh the risks and benefits carefully. Clinical and immunological status should be considered before suggesting a total knee replacement to a haemophilic patient. If TKA is contraindicated, knee arthrodesis is the alternative. However, knee joint debridement can relieve pain for several years and delay the need for TKA.
Haemophilia 2002: emerging risks of treatment
Authors: EVATT B. L. , FARRUGIA A. , SHAPIRO A. D. , WILDE J. T.
Published: March 2003

Haemophilia care and treatment products have greatly improved over the past 2 decades. Transitions in treatment produced by these changes were accompanied by the emergence of unexpected risks and new complications. In order to provide the best comprehensive care to patients with haemophilia, healthcare providers periodically need to re‐evaluate and adjust their management and therapeutic products to prevent or minimize the effects produced by the emerging issues. For example, reducing the effects of infectious agents remains the highest priority for the haemophilia community because of the high level of morbidity and mortality that has resulted from earlier therapeutic agents. In many countries, the goal has been to achieve absolute zero risk for infectious agents. In some instances, the screening procedures to achieve these goals reduced the availability of plasma needed for manufactured derivatives and produced another emerging risk, shortages of clotting factor preparations. Similarly, better diagnostic methods identified other potential agents that were not inactivated by current technology. Likewise, immune tolerance regimens and the prophylactic management of haemophilia introduced different therapeutic delivery systems with their own risks. The drugs used to manage diseases such as human immunodeficiency virus (HIV), which were transmitted by products manufactured before mid‐1980, create their own set of risks for this community.

Topical emerging risks of treatment, including variant Creutzfeldt–Jakob disease, an assessment of its risks and impact, the complications of using indwelling catheters, and the role of protease inhibitors used to treat HIV may have on bleeding complications of haemophilia are discussed.
Orthoses in haemophilia
Authors: Querol F. , Aznar J. A. , Haya S. , Cid A.
Published: March 2003

Summary.  In haemophilia patients, orthoses are used for the prevention and management of bleeds and their effects on the musculoskeletal system. The characteristics of these devices vary according to the joint to which they are applied, although two basic types are distinguished: static and functional. The upper limbs make up a functional unit that is adapted to prehension, or the action of grasping or seizing objects. The most affected joints of this unit in haemophilia are the elbow and shoulder, which require immobilization, followed by stabilization and protection and in the case of disability, assistance in the performance of function. The lower limbs, on the other hand, are adapted to the action of ambulation. The knee, ankle and hip joints frequently sustain damage in haemophilia, and in the acute phase they should be immobilized and the patient discouraged from walking. Once bleeding has ceased, and motion and muscle balance improved, a gradual return to normal activity may commence. The principle aim of orthotics in these cases is to immobilize and unburden the affected body segment, and to provide stability and assistance for ambulation. Shoe insoles cushion and modify stance, and therefore may help prevent lesions. Crutches and walking frames are used for restoring normal gait. Orthotic devices improve the quality of life of haemophilia patients with musculoskeletal lesions and are useful for preventing lesions resulting from strenuous activities, whether performed in the course of daily living or in the pursuit of games and sports.
Sexuality and haemophilia: connections across the life‐span
Authors: Parish K. L.
Published: March 2003

Summary.  A broad overview of sexuality issues and needs as they relate to haemophilia are presented. Venturing well beyond ‘safer sex’, sexuality is defined here to encompass physical, emotional, social, interpersonal, moral, and cultural aspects. From this perspective, sexuality extends beyond behaviour and includes a person's thoughts, feelings, nature, and identity. As a means of experiencing intimacy, sexuality is a significant factor in achieving quality of life with chronic illness. Its impact in haemophilia is influenced by different stages of physical and psychosexual development, misconceptions about sexuality, and unique concerns for this group, including joint disability, human immunodeficiency virus, medication side‐effects, and other complications. This paper explores the interconnections of sexuality with haemophilia, with a focus on the roles that haemophilia care providers can play in addressing these issues. A biopsychosocial model of aspects and interrelationships regarding sexuality and haemophilia is proposed for use in understanding individuals and planning care approaches. The PLISSIT model is offered to guide counselling about sexuality on different levels of complexity. Sample strategies for initiating discussion, communicating about sex, and developing goals and interventions are presented.
Clinical efficacy of highly purified, doubly virus‐inactivated factor VIII/von Willebrand factor concentrate (Fanhdi®) in the treatment of von Willebrand disease: a retrospective clinical study
Authors: Federici A. B. , Baudo F. , Caracciolo C. , Mancuso G. , Mazzucconi M. G. , Musso R. , Schinco P. C. , Targhetta R. , Mannucci P. Mannuccio
Published: March 2003

Summary. The goal of therapy in patients with von Willebrand disease (vWD) is to correct the dual defect of primary haemostasis and intrinsic coagulation reflected by low levels of von Willebrand factor (vWF) and factor VIII coagulant activity (FVIII:C). Factor VIII/von Willebrand factor (FVIII/vWF) concentrates are currently the treatment of choice in vWD patients unresponsive to desmopressin (DDAVP). However, only few studies on their clinical use are available so far. The main objective of this study was to retrospectively evaluate the clinical efficacy of a highly purified, doubly virus‐inactivated FVIII/vWF concentrate with a high content of FVIII/vWF (Fanhdi®). Twenty‐two patients with congenital vWD have been treated from 1999 to 2001 at eight specialized centres belonging to the Italian Association of Hemophilia Centers (AICE). Ten males and 12 females, median age 28.5 years, range 5–70 years) had type 3 vWD (six cases), DDAVP‐unresponsive type 1 (nine cases) and type 2B (seven cases). The study drug was given to stop or prevent 12 bleeding episodes or to prevent excessive bleeding during 14 surgical or invasive procedures. Overall, replacement therapy with the concentrate showed an excellent to good clinical efficacy in 92% of bleeding episodes and in 93% of surgical procedures. No adverse events occurred during 1601 infusions, accounting for a total of 304 500 IU of FVIII:C administered. These results confirm the efficacy and safety of this concentrate in the management of bleeding episodes and in the prevention of excessive bleeding during major and minor surgery.
Overall haemostatic potential can be used for estimation of thrombin‐activatable fibrinolysis inhibitor‐dependent fibrinolysis in vivo and for possible follow‐up of recombinant factor VIIa treatment in patients with inhibitors to factor VIII
Authors: Antovic J. P. , Antovic A. , He S , Tengborn L. , Blombäck M.
Published: March 2003

Summary. Thrombin generation induced by recombinant factor VIIa (rFVIIa) in patients with haemophilia and/or inhibitors to factor VIII/IX could enhance generation of thrombin‐activatable fibrinolysis inhibitor (TAFI), a recently described link between coagulation and fibrinolysis. TAFI is unstable and it is not easy to measure its active form in vivo. Overall haemostatic potential (OHP) is a novel method for haemostasis estimation, based on determination of the fibrin aggregation curve in which tiny amounts of thrombin are used for activation of clotting. We measured OHP in six patients with inhibitors to factor VIII before injection of rFVIIa and 10 and 120 min thereafter. Overall fibrinolytic potential (OFP) and clot lysis time (CLT) analysed by this method could be used for indirect estimation of TAFI generation. We found no change in pro‐TAFI and total TAFI antigen before and after treatment with rFVIIa. OHP was almost undetectable before treatment but increased into the range of normal pooled plasma 10 and 120 min after rFVIIa treatment, as did CLT. However, after addition of potato tuber carboxypeptidase inhibitor, a specific inhibitor of TAFI, the shortening of CLT was lower than that in NPP. OFP was increased in patient plasma both 10 and 120 min after treatment compared with NPP. There was a strong positive correlation between pro‐TAFI concentration and shortening of CLT after PTCI addition and a negative correlation between pro‐TAFI concentration and OFP 10 min after rFVIIa injection. Thus, rFVIIa normalizes OHP and CLT 10 min after injection. While this improvement slightly decreases, but still exists after 2 hours, it suggests efficacy in bleeding prevention using a protocol based on rFVIIa administration every 2 hours.
Prophylactic treatment for severe haemophilia: comparison of an intermediate‐dose to a high‐dose regimen
Authors: Fischer K. , Astermark J. , Van Der Bom J. G. , Ljung R. , Berntorp E. , Grobbee D. E. , Van Den Berg H. M.
Published: March 2003

Summary.  A multicentre study was performed in Sweden and the Netherlands, comparing effects of two prophylactic regimens in 128 patients with severe haemophilia, born 1970–90. 42 Swedish patients (high‐dose prophylaxis), were compared with 86 Dutch patients (intermediate‐dose prophylaxis). Patients were evaluated at the date of their last radiological score according to Pettersson. Annual clotting factor consumption and bleeding frequency were registered for a period of three years before evaluation. Patients in the high‐dose group were younger at evaluation (median 15.2 vs. 17.9 years), started prophylaxis earlier (median 2 vs. 5 years), and used 2.19 times more clotting factor kg−1 year−1. Patients treated with high‐dose prophylaxis had fewer joint bleeds (median 0.3 year−1 vs. 3.3 year−1) and the proportion of patients without arthropathy as measured by the Pettersson score was higher (69% vs. 32%), however, the age‐adjusted difference in scores (median 0 points vs. 4 points) was small and at present not statistically significant. Clinical scores and quality of life were similar. These findings suggest that, compared with intermediate‐dose prophylaxis, high‐dose prophylaxis significantly increases treatment costs and reduces joint bleeds over a period of 3 years, but only slightly reduces arthropathy after 17 years of follow‐up.
Viral pharmacovigilance study of haemophiliacs receiving porcine factor VIII
Authors: Giangrande P. L. F. , Kessler C. M. , Jenkins C. E. , Weatherill P. J. , Webb P. D.
Published: March 2003

Summary.  Porcine factor VIII (FVIII; Hyate:C; Speywood Biopharm Ltd, UK) has been used since 1980 for the treatment both of patients with acquired haemophilia and those with congenital haemophilia and inhibitory antibodies. Each batch is extensively screened using cell‐culture techniques to confirm the absence of viruses. The production process does not incorporate specific virucidal treatment steps, such as heat treatment or the addition of a solvent/detergent mixture. Low levels of porcine parvovirus were detected in some batches of the product in late 1996 and supply was suspended. In this retrospective study, sera from 81 recipients of porcine FVIII and 125 other volunteers were screened for evidence of antibodies against a range of porcine viruses: porcine parvovirus (PPV), encephalomyocarditis virus (EMCV), and porcine respiratory and reproductive syndrome virus (PRRSV). The 125 volunteer controls included subjects from six categories: healthy control subjects, pig abattoir personnel, personnel involved in the manufacture of porcine FVIII, recipients of porcine heparin, recipients of porcine insulin, and haemophiliacs treated only with human FVIII. No antibodies to PPV or PRRSV were detected in any subject. Four patients and two volunteers were found to have antibodies to EMCV, but this incidence is similar to that observed in the general population. In conclusion, there was no evidence of transmission of PPR or other marker porcine virus associated with the use of porcine FVIII concentrate (Hyate: C).
Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von Willebrand's disease
Authors: Gomez García E. B. , Ruitenberg A. , Madretsma G. S. , Hintzen R. Q.
Published: March 2003

Summary.  A middle‐aged woman was admitted to the hospital after being found unconscious at home. A brain CT scan excluded an intracranial bleed or other focal abnormality. Laboratory analysis showed hyponatraemia (sodium: 121 mmol L−1) and a low plasma osmolality, with normal sodium excretion and urine osmolality. A diagnosis of hyponatraemic coma was made. The patient was treated with water restriction; 24 h later the sodium was 135 mmol L−1 and the patient was neurologically fully recovered. The patient, who suffered from von Willebrand's disease, had received desmopressin and ibuprofen for analgesia 2 days before after a dental intervention. She had received desmopressin several times in the past without any complications. A few patients treated with desmopressin for coagulation abnormalities have been reported to develop water intoxication and severe hyponatraemia resulting in seizures and coma. By inhibiting prostaglandin synthesis, non‐steroid anti‐inflammatory agents (NSAIDs) potentiate the effect of water reabsorption in the renal tubules of vasopressin, therefore enhancing water retention. Desmopressin and NSAIDs should not be used in combination in patients with bleeding disorders, but it is often followed in clinical practice. In addition, this is probably not an unusual situation in patients treated with desmopressin for other ‘non‐haemorrhagic’ indications. This report emphasizes the need for practitioners to be aware of this rare but severe complication.
Dynamic global vegetation modelling for prediction of plant functional types and biogenic trace gas fluxes
Authors: Potter Christopher S. , Klooster Steven A.
Published: March 2003

1. A Dynamic Global Vegetation Model (DGVM) has been developed as a new feature of the NASA‐CASA (Carnegie Ames Stanford Approach) ecosystem production and trace gas model. This DGVM includes seasonal phenology algorithms calibrated using historical interannual data sets derived from the Advanced Very High Resolution (AVHRR) satellite ‘greenness’ index.

2. The coupled CASA‐DGVM design is based conceptually on two main elements of Tilman's resource‐ratio hypothesis of vegetation change, namely: 1) plant competition for resources (water and light) over relatively short time periods of months and seasons; and 2) the long‐term pattern in the supply of growth‐limiting resources such as water and nutrients, i.e. the resource‐supply trajectory. This simulation model generates global gridded estimates of primary production, above and below ground biomass, leaf area index (LAI), and trace gas fluxes from soil.

3. Eight distributed test locations for the DGVM were evaluated initially to represent a variety of climate conditions ranging from Arctic (64°N Alaska) to tropical and subtropical (24°S southern Africa) latitude zones. At all test locations, the predicted plant functional type (PFT) matched closely with the actual reported PFT.

4. In the process of running the model to steady state PFTs, most forest locations showed a rapid progression of transient states, from bare ground to grassland, to grasses with shrub cover, and finally to the forest PFT. From this first global application, the DGVM correctly predicts the presence of forest classes in approximately 75–95% of all cases worldwide, and grasslands in approximately 58% of all cases.

5. The effects of two hypothetical climate change scenarios were evaluated. Scenario I was set by warming air surface temperatures linearly to 4 °C above average over a 25‐year simulation period. Scenario II was set by decreasing annual rainfall amounts linearly to 50% below average over a 25‐year simulation period.

6. The warming scenario I resulted in PFT at high‐latitude forest and boreal forest sites changing to mixed coniferous forest, accompanied by increase in canopy LAI. The drought scenario II resulted in PFT at the boreal forest and savanna sites changing to grasslands. At locations where PFT did not change with climate, however, soil water and canopy LAI were predicted to decline progressively under the warming scenario, beginning from steady‐state temperate and tropical zone PFTs. They also declined under the drought scenario beginning from practically any steady state PFT.
Annual and interannual CO2 exchanges of the terrestrial biosphere: process‐based simulations and uncertainties
Authors: Knorr Wolfgang
Published: March 2003

Assessments of climate change impacts on the global carbon cycle have to rely on accurate models describing the contribution of the terrestrial biosphere. Interannual climate fluctuations provide an ideal test case for their reliability because results can be checked against atmospheric measurements.
Simulated responses of potential vegetation to doubled‐CO2 climate change and feedbacks on near‐surface temperature
Authors: Betts Richard A. , Cox Peter M. , Woodward F. Ian
Published: March 2003

Increases in the atmospheric concentration of carbon dioxide and associated changes in climate may exert large impacts on plant physiology and the density of vegetation cover. These may in turn provide feedbacks on climate through a modification of surface‐atmosphere fluxes of energy and moisture. This paper uses asynchronously coupled models of global vegetation and climate to examine the responses of potential vegetation to different aspects of a doubled‐CO2 environmental change, and compares the feedbacks on near‐surface temperature arising from physiological and structural components of the vegetation response. Stomatal conductance reduces in response to the higher CO2 concentration, but rising temperatures and a redistribution of precipitation also exert significant impacts on this property as well as leading to major changes in potential vegetation structure. Overall, physiological responses act to enhance the warming near the surface, but in many areas this is offset by increases in leaf area resulting from greater precipitation and higher temperatures. Interactions with seasonal snow cover result in a positive feedback on winter warming in the boreal forest regions.
The paradox of invasion
Authors: Sax Dov F. , Brown James H.
Published: March 2003

It is paradoxical that exotic species invade and displace native species that are well adapted to local environments. Yet, even those exotics that eventually become abundant and widespread, often do so only after having failed to establish following multiple earlier introductions. The first pattern, while not generally discussed in this context, is usually explained by exotic species pre‐adaptations for human‐altered environments and by a release from enemies. It can be understood further by examining the superior quality of colonists from large species‐rich regions and the historical contingency of evolution. The second pattern is generally explained by invoking demographic and environmental stochasticity; however, it can be understood further by examining the role of environmental variation over space and by metapopulation dynamics. These processes provide a context in which these patterns of invasion are not paradoxical, but instead, expected.
Negative association of Enterobius infestation with asthma and rhinitis in primary school children in Taipei
Authors: Huang S.‐L. , Tsai P.‐F. , Yeh Y.‐F.
Published: March 2003

Background The relationship between allergy and parasites has been controversial, especially in non‐tropical countries. Enterobius vermicularis (human pinworm) is the most prevalent intestinal parasite in industrialized countries.

Objective To examine the association between pinworm infestation and allergy in primary school children.

Method Peri‐anal tape test for pinworm is routinely performed in Taipei primary schools. We collected data from school records and questionnaires distributed to all children in four primary schools grades 1 through 6 (n = 3107).

Results The prevalence of physician‐diagnosed asthma (9.3% vs. 14.1%, P = 0.007) and allergic rhinitis (27.4% vs. 38.3%, P = 0.001) was lower in pinworm‐positive compared to uninfested children. Pinworm was not correlated with atopic dermatitis or parent allergy. With logistic regression controlling for sex, parent allergy and lower respiratory infection, current asthma (OR = 0.25, 95% CI 0.10–0.63) and rhinitis (OR = 0.61, 95% CI 0.45–0.84) were negatively associated with pinworm. Among children in grades 3–6 who had no asthma or rhinitis before age 7, those with early infestation (pinworm diagnosis at or before grade 1) had a lower risk of having diagnosis of rhinitis during school years, compared to the uninfected group (5.4% vs. 12.3%, P = 0.03; adjusted OR = 0.47, 95% CI 0.21–1.02).

Conclusions We identified a negative association between pinworm infestation and allergic airway diseases, which could in part be attributed to protective effect of pinworm infestation on development of allergic symptoms. Other mechanisms of association could not be ruled out.
The correlation between ovomucoid‐derived peptides, human leucocyte antigen class II molecules and T cell receptor‐complementarity determining region 3 compositions in patients with egg‐white allergy
Authors: Suzuki K. , Inoue R. , Sakaguchi H. , Aoki M. , Kato Z. , Kaneko H. , Matsushita S. , Kondo N.
Published: March 2003

Background Food allergies are more prevalent in children, due to the immature gastrointestinal epithelial membrane barrier allowing more proteins through the barrier and into circulation. Ovomucoid (OM) is one of the major allergens that is found in egg white.

Objective The aim of this study was to determine T cell epitopes, antigen‐presenting human leucocyte antigen (HLA) class II molecules of the T cell lines (TCLs) and T cell clones (TCCs), and complementarity determining region (CDR) 3 loops of the T cell receptor (TCR) α and β chains of the TCCs specific to OM.

Methods We established TCLs and TCCs specific to OM from peripheral blood mononuclear cells (PBMCs) of four atopic patients with egg‐white allergy using a mixture of a panel of overlapping synthetic peptides corresponding to the amino acid sequence of the entire OM. We identified the T cell epitopes by antigen‐induced proliferative responses, antigen‐presenting molecules using allogeneic PBMCs and CDR3 loops of the TCR α and β chains by cloning and sequence analysis.

Results The TCLs and TCCs responded to seven different peptides, and their antigen‐presenting molecules were different from each other. Sequence analysis of the TCR α and β gene usage of the TCCs showed marked heterogeneity, and the usage of the CDR3 loop of the TCCs involved heterogenous amino acid residues. Interestingly, TCCs ‘IH3.3’ and ‘YT6.1’ recognized the same OM peptides, and had the same TCR Vβ‐Jβ gene usage. Considering that peptide motifs bind to HLA class II molecules, the electrically charged residue (positive or negative) on the CDR3α and the CDR3β loops of TCR of TCC may form ionic bonds with a charged residue on the HLA class II molecules‐peptide complex.

Conclusions TCCs that have the same TCR gene usage were established from patients who had shown similar hypersensitivity‐type, indicating that antigen recognition by a specific TCR is closely associated with the characteristics of each patient's symptoms.
Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients
Authors: Tohda Y. , Fujimura M. , Taniguchi H. , Takagi K. , Igarashi T. , Yasuhara H. , Takahashi K. , Nakajima S.
Published: March 2003

Background Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma.

Objective To determine whether the addition of montelukast could lead to a reduction in inhaled corticosteroid dose without a significant decrease in peak expiratory flow rate (PEFR).

Methods After a 4‐week run‐in period, 191 moderate‐to‐severe asthmatic patients whose asthma had been well controlled with daily inhaled corticosteroid therapy (beclometasone dipropionate 800 to 1600 µg/day), were randomly assigned to one of two treatments – placebo (n = 98) or montelukast 10 mg once daily (n = 93) – for a 24‐week, multicentre, double‐blind, treatment period. At the beginning of the active treatment period, the daily dose of inhaled corticosteroid was halved in all of the patients. In addition, the inhaled corticosteroid dose was subsequently titrated every 8 weeks, based on PEFR, asthma symptoms and β‐agonist use.

Results After 8 weeks of a 50% reduction in inhaled corticosteroid use, morning PEFR increased by 5.3 ± 32.3 L/min from baseline in patients receiving montelukast and significantly decreased by 6.9 ± 29.0 L/min in those receiving placebo (P = 0.035). In addition, evening PEFR significantly decreased by 9.8 ± 28.5 L/min (P = 0.003) in the placebo group, but was maintained in the montelukast group. In spite of a subsequent 50% reduction in the inhaled corticosteroid dose every 8 weeks, morning and evening PEFRs were maintained over the 24‐week treatment period in the montelukast group; PEFR significantly decreased in the placebo group. There was a significant difference between the two groups with regard to morning PEFR, therapy score and asthmatic score at weeks 8, 16 and 24, as well as evening PEFR at week 8. However, the symptom scores were not significantly different between the two groups or within each group.

Conclusion These data suggest that montelukast reduces the need for inhaled corticosteroids while maintaining asthma control over a 24‐week period. Therefore, montelukast may be useful for long‐term treatment in patients with asthma who require high doses of inhaled corticosteroids.
Prevalence of endothelial nitric oxide synthase gene polymorphisms in patients with atopic asthma
Authors: Hollá L. I. , Bučková D. , Kuhrová V. , Stejskalová A. , Francová H. , Znojil V. , Vácha J.
Published: March 2003

Background Asthma is a common multifactorial disease, the aetiology of which is attributable to both environmental and genetic factors. The endothelial nitric oxide synthase (NOS3) gene has been implicated in asthma pathogenesis.

Objective This study investigated associations of 27 base‐pair tandem repeat polymorphism in intron 4 and the Glu298Asp (G894T) variant of the NOS3 gene with atopic asthma in a Czech population.

Methods Polymerase chain reaction was used to determine the NOS3 genotypes in subjects with atopic asthma (n = 163) and random controls (n = 209).

Results The NOS3 allele or genotype distributions did not differ significantly between the control and asthma groups. However, the common genotype (bb) of the NOS3 polymorphism in intron 4 was found to be significantly associated with total IgE levels (P = 0.006), specific IgE levels for feathers (P = 0.0002) and a positive skin prick test for hay (P = 0.004). In one atopic patient, we identified an additional 27‐bp repeat in the NOS3 gene (NOS3c), which occurred in heterozygous combination with the NOS3b allele (NOS3b/c genotype). In addition, we describe a new polymorphism (A5495G) in the NOS3 gene, which was in almost complete linkage disequilibrium with the NOS3 repeat polymorphism in intron 4. The Glu298Asp variant was not associated with asthma and/or related atopic phenotypes in our study.

Conclusion Neither the NOS3 ‘b’ allele nor the NOS3 ‘b/b’ genotype showed any general association with atopic asthma, but they were associated with atopy‐related phenotypes. We conclude that the NOS3 gene polymorphisms may act as disease modifiers in atopic asthma phenotype in our population.
Expression and function of the ST2 gene in a murine model of allergic airway inflammation
Authors: Oshikawa K. , Yanagisawa K. , Tominaga S. , Sugiyama Y.
Published: March 2003

Background We have recently reported that soluble ST2 protein levels are elevated in the sera of patients with asthma, and correlate well with the severity of asthma exacerbation. However, the role, function, and kinetics of soluble ST2 expression in asthma remain unclear.

Objective The objective of the present study was to clarify the function and kinetics of soluble murine (m) ST2 expression in a murine asthma model.

Methods We analyzed the kinetics of gene and protein expression of mST2 in sera or lung tissue after allergen (ovalbumin; OVA) challenge in a murine model of allergic airway inflammation, the effects of mST2 protein on OVA‐induced Th2 cytokine production in vitro from splenocytes of sensitized mice, and the effects of soluble mST2 on Th2‐dependent allergic airway inflammation by in vivo gene transfer of mST2.

Results Serum mST2 protein levels increased to the maximal level 3 h after the allergen challenge, before serum IL‐5 levels peaked. The mRNA expression of mST2 in lung tissue was induced after the allergen challenge, while that in the spleen was constitutively detected. Furthermore, pre‐treatment with mST2 protein significantly inhibited the production of IL‐4 and IL‐5, but not IFN‐γ, from OVA‐stimulated splenocytes in vitro, and intravenous mST2 gene transfer resulted in a drastic reduction in the number of eosinophils and in the levels of IL‐4 and IL‐5 in bronchoalveolar lavage fluid, compared with those in response to transfer of non‐coding plasmid vector or of lipid alone.

Conclusion These results suggest that increases in endogenous mST2 protein after allergen exposure may modulate Th2‐mediated airway inflammation, and that in vivo gene transfer of mST2 can be applicable to use in a novel immunotherapy for allergic diseases.
A comparative study of eicosanoid concentrations in sputum and urine in patients with aspirin‐intolerant asthma
Authors: Higashi N. , Taniguchi M. , Mita H. , Osame M. , Akiyama K.
Published: March 2003

Background Although many studies have assumed that the overproduction of cysteinyl‐ leukotrienes (cys‐LTs) and an imbalance of arachidonic acid metabolism may be plausible causes for the pathogenesis of aspirin‐intolerant asthma (AIA), there has been little experimental evidence to substantiate this notion in lower airways of patients with AIA.

Objectives The purpose of this study was to compare the eicosanoid concentrations in sputum and urine from patients with AIA.

Methods The concentrations of sputum cys‐LTs, prostaglandin E2 (PGE2), PGF2α, PGD2 and thromboxane B2 were measured to assess local concentrations of eicosanoids in patients with AIA and in those with aspirin‐tolerant asthma (ATA). The concentrations of two urinary metabolites, leukotriene E4 (LTE4) and 9α11βPGF2, were also measured to corroborate the relationship between the eicosanoid biosynthesis in the whole body and that in lower airways.

Results The concentration of PGD2 in sputum was significantly higher in patients with AIA than in those with ATA (median, 5.3 pg/mL vs. 3.1 pg/mL, P < 0.05), but there was no significant difference in the concentration of the corresponding metabolite, 9α11βPGF2, between the two groups. No differences were noted in the concentrations of other prostanoids in sputum between the two groups. The sputum cys‐LT concentrations showed no differences between the two groups, in spite of the observation that the concentration of urinary LTE4 was significantly higher in patients with AIA than in those with ATA (median, 195.2 pg/mg‐cre vs. 122.1 pg/mg‐cre, P < 0.05). There was a significant correlation among the concentration of cys‐LTs, the number of eosinophils and the concentration of eosinophil‐derived neurotoxin (EDN) in sputum.

Conclusion The urinary concentration of LTE4 does not necessary reflect cys‐LT biosynthesis in lower airways. A significantly higher concentration of PGD2 in sputum from patients with AIA suggests the possible ongoing mast cell activation in lower airways.
Are ecological and evolutionary rules being dismissed prematurely?
Authors: Ashton Kyle G.
Published: March 2003

Recently, it has been suggested that the group of patterns known as the ecological and evolutionary rules are invalid and only of interest historically. Here, I briefly review evidence for the four most prominent patterns: Bergmann’s rule, Cope’s rule, Rapoport’s rule, and the latitudinal gradient in species richness. Although more comprehensive reviews exist for these patterns, the purpose of this paper is to highlight recent work illustrating the validity of each pattern, to question the conclusion that these patterns are only of historical interest, and to briefly explore possible connections between each of these patterns. I also recommend that meta‐analytical techniques, a group of statistical methods rarely used in ecology and evolution, need to be incorporated in future tests of general trends.
Cenozoic environmental change in South America as indicated by mammalian body size distributions (cenograms)
Authors: Croft Darin A.
Published: March 2003

A cenogram is a rank‐ordered body size distribution of non‐predatory terrestrial mammal species within a community. Studies of cenograms for modern faunas have shown that certain quantifiable attributes of cenograms are correlated with environmental variables such as rainfall and vegetation structure. Based on these correlations, cenograms of fossil communities have been used to infer palaeoenvironments and palaeoenvironmental variables. The present study uses cenogram statistics to interpret palaeoenvironmental conditions for eight Cenozoic South American mammal faunas, ranging from Eocene to Pleistocene in age. Body sizes for fossil taxa were taken either from the literature or were estimated using regressions of body size on molar length (or femoral bicondylar width) for modern mammals. Cenogram statistics are calculated for the eight fossil faunas and compared to similar statistics calculated for 16 modern South American mammal faunas, allowing palaeoenvironmental interpretations to be made. The palaeoenvironmental interpretations based on cenogram analyses sometimes support and sometimes contradict interpretations based on herbivore craniodental morphology (e.g. levels of hypsodonty). Simulations of expected errors in body size estimates for fossil taxa suggest that the discrepancies do not result primarily from erroneous body size estimates. It is possible that some of the incongruity in interpretations results from certain non‐analogue attributes of South American faunas during much of the Cenozoic (e.g. the relatively depauperate mammalian predator diversity prior to the Great American Biotic Interchange).