bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful surgical treatment of haemophilic pseudotumour, filling the defect with hydroxyapatite
Authors: Sagarra  , Lucas  , De La Torre  , Almagro  , González  , García  , Menéndez  , González
Published: March 2003

A preliminary report is made on the use of hydroxyapatite for surgical procedure of pseudotumour, a rare but serious complication of the bleeding diathesis in patients with inherited bleeding disorders. Surgical or percutaneous treatment and refilling with fibrin sealant is shown to be a successful therapy in a 19‐year‐old male with severe haemophilia B. The pseudotumour, in the upper pad of the left leg, was filled with hydroxyapatite after surgery. We suggest that the use of hydroxyapatite is a new and useful option in the surgical treatment of haemophilic pseudotumour.
Iliopsoas haemophiliac pseudotumours with bowel fistulation
Authors: Heaton  , Robertson  , Rothwell
Published: March 2003

Two cases of iliopsoas haemophilic pseudotumours are presented. In one patient a fistula developed between a pseudotumour and the large bowel. This resulted in an abscess involving the pseudotumour and adjacent tissues. It resolved after 5 years of therapy involving percutaneous drainage and closure of the fistula. The second patient had a massive pseudotumour that had obstructed both ureters. Later he suffered a fatal mixed Gram negative septicaemia probably related to erosion into the colon.
Haemophilia care in central Scotland 1980–94. I. Demographic characteristics, hospital admissions and causes of death
Authors: Ludlam  , Lee  , Prescott  , Andrews  , Kirke  , Thomas  , Chalmers  , Lowe
Published: March 2003

To estimate the resources required to manage patients with haemophilia in Scotland, we studied the demographic features, hospital admissions and causes of deaths for individuals with haemophilia A and B and von Willebrand disease, treated with blood products, during the period 1980–94 living in central Scotland. Data were obtained from 413 adults and children (93% ascertainment). The age distribution in 1980 revealed a paucity of individuals over 60 years but the number in this age group increased over the study period. Of those with haemophilia A and B, 63 and two respectively, became HIV positive. Hospital admissions rose from 103 to 168 per annum; the number of annual bed days utilized also increased, but there was marked annual fluctuation (790–1832). The rate of admission was greater for those with severe haemophilia A and this increased during the 15‐year period mainly due to the clinical consequences of human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The admission rate for haemophilia B was significantly lower than that for haemophilia A, and was similar for all degrees of severity of the disorder. Throughout the 15‐year period the incidence of admissions for acute bleeds was constant, as was the average duration in hospital. For those with a factor VIII inhibitor, the rate of admission was about double the rate of those without an inhibitor, although the duration of hospital stay was similar for both groups. There were 61 deaths; the death rate increased during the study period principally due to HIV and HCV, and 12 patients died from haemorrhage. We conclude that: (i) the life expectancy for haemophiliacs in Scotland was generally increasing, although HIV and HCV caused increasing mortality and morbidity (as shown by the increase in hospital admissions); (ii) hospital bed usage for the treatment of acute bleeds continued to be required, but fluctuated greatly; and (iii) the clinical impression that haemophilia B is less clinically severe than haemophilia A is confirmed by objective data. The planning implications for haemophilia care in Scotland and similar countries are discussed.
In vitro stability of recombinant human factor VIII (Recombinate™)
Authors: Parti  , Ardosa  , Yang  , Mankarious
Published: March 2003

Factor VIII (FVIII) is currently administered in diverse settings and by a range of methods, and it is important that the stability of specific FVIII preparations be documented for these varying uses. This study of Recombinate™ recombinant human FVIII (rhFVIII) evaluated: (i) thermostability; (ii) photostability; (iii) stability during simulated continuous infusion; and (iv) stability after dilution. This evaluation was conducted over a range of initial rhFVIII potencies and under differing conditions of temperature, light exposure, dilution and heparin usage. FVIII biological activity was measured by one‐stage and chromogenic substrate assays. Microbiological assessment was also performed. Lyophilized rhFVIII was found to be highly thermostable, as evidenced by an energy of activation (Ea) of 16.2 kcal mol–1 and recovery of 99.3% of initial activity after incubation for 6 months at 40 °C and 93.8% at 60 °C for 2 months. No significant loss of activity could be detected after accelerated simulated natural daylight exposure of lyophilized rhFVIII, although partial activity loss was observed after similar exposure of reconstituted rhFVIII. Shielding in foil wrap effectively prevented such photodegradation of reconstituted rhFVIII. Based upon these results, exposure of lyophilized rhFVIII to sunlight is unlikely to affect stability adversely. Activity of reconstituted rhFVIII (22–106 IU mL–1) remained stable during simulated continuous infusion for 96 h at ambient (20–25 °C) and elevated (28–32 °C) temperature, and in the presence or absence of 1 U mL–1 heparin. After dilution of reconstituted rhFVIII, an immediate 14–42% loss of expected rhFVIII activity was observed depending upon diluent composition. Accordingly, potential partial loss of rhFVIII activity should be taken into account when dilution is being considered. rhFVIII remained sterile at least 96 h during simulated continuous infusion. rhFVIII is a robust preparation exhibiting biological stability under a wide array of clinically relevant conditions.
Immune tolerance for haemophilia patients with inhibitors: analysis of the western United States experience
Authors: Damiano  , Hutter  ,   THE TRI‐REGIONAL NURSING GROUP
Published: March 2003

The experience with immune tolerance (IT) induction therapy for haemophilia patients with inhibitors, instituted during 1990–97 at 17 haemophilia treatment centres in the western United States, was reviewed. IT was instituted in 104 of 139 (75%) of all identified haemophilia A and haemophilia B patients with inhibitors. Doses and schedules for IT varied but most patients were treated with a daily administration of 25–200 units kg–1 day–1. Successful immune tolerance (defined as Bethesda Unit titres < 1.0) was achieved in 57 of 81 (78%) patients who completed therapy. IT success was significantly greater for those patients with historic titres < 100 BU (P < 0.0003) and those with titres of < 10 BU at initiation of IT (P < 0.0001). IT success was uniformly achieved in 16 patients with low to moderate responding inhibitors. IT in infants < 2 years of age was problematic due to the presence of high titre inhibitors and complications of venous access. Frequent complications of IT included increased bleeding during intravenous access device insertion (20%) and infections associated with venous access devices (64%). IT is widely accepted as a treatment modality for haemophilia patients with inhibitors. Patient participation in IT regimens and management during therapy is facilitated greatly by the efforts of treatment centre nurse co‐ordinators who are knowledgeable about haemophilia and its complications. Additional clinical trials will be necessary to define better initial dose, schedule, dose adjustment and success/failure criteria for IT.
Massive bleeding from a gastric erosion after transcatheter arterial chemoembolization for hepatocellular carcinoma in a patient with mild haemophilia A
Authors: Toyoda H. , Fukuda Y. , Nakano I. , Katano Y. , Ebata M. , Nagano K‐I. , Morita K. , Yokozaki S. , Takeuchi M. , Hayakawa T. , Takamatsu J.
Published: March 2003

We observed massive bleeding from a gastric erosion following transcatheter arterial chemoembolization (TAE) in a patient with mild haemophilia A. A 78‐year‐old haemophiliac (factor VIII level over 60%) received TAE with farmorubicin and spongel. Haematemesis and melena with loss of consciousness occurred 9 days after TAE, and endoscopy revealed superficial erosions with oozing. Toxic effects of the anticancer drug in conjunction with the bleeding disorder may have caused the massive bleeding. We should always consider the possibility of unexpected complications in patients with bleeding disorders; gastrointestinal bleeding can develop during treatment for liver tumours.
Yttrium‐90 synoviorthesis for chronic haemophilic synovitis: Madrid experience
Authors: Rodriguez‐Merchan E.C. , Jimenez‐Yuste V. , Villar A. , Quintana M. , Lopez‐Cabarcos C. , Hernandez‐Navarro F.
Published: March 2003

Between 1994 and 1999 we performed 66 Yttrium‐90 (90Y) synoviortheses on 44 persons with haemophilia (45 knees, 12 elbows, nine ankles). At the time of injection 23 patients were HIV+ and two had inhibitors. The average age was 21.1 years (range: 9–39). Five mCi of 90Y were injected into the knees, and 3 mCi into the elbows and ankles. The average follow‐up was 3.5 years (range: 1–6). Of the 45 knees, there were eight excellent, 10 good, 15 fair and 12 poor results. Of the 12 elbows there were three excellent results, five good, three fair and two poor. Of the nine ankles there were no excellent results, four good, three fair and two poor. The elbows had better results than the knees and ankles. The best results were obtained in the youngest patients, and in those with a moderate degree of synovitis, regardless of their HIV status and the presence of inhibitor. 90Y synoviorthesis should be performed in very young patients, when the amount of synovium is still moderate. Once the degree of synovitis has become severe, the expected results of radioactive synoviorthesis are worse.
Home‐based factor infusion therapy and hospitalization for bleeding complications among males with haemophilia
Authors: Soucie J. M. , Symons J. , Evatt B. , Brettler D. , Huszti H. , Linden J. ,   THE HEMOPHILIA SURVEILLANCE SYSTEM PROJECT INVESTIGATORS
Published: March 2003

Information from the medical records of 2650 US males with haemophilia living in six states was used to examine the influence of infusing factor concentrate at home (home therapy) and other variables on rates of hospitalization for a haemorrhagic bleeding complication (HBC) over a 4‐year period. Bleeding complications included actual and suspected haemorrhagic events but excluded elective admissions for procedures necessitated by haemorrhage (e.g. joint synovectomy). Other risk determinants considered in the analyses included age, race, employment status, health insurance type, care received in federally funded haemophilia treatment centres (HTCs), factor deficiency type and severity, amount of factor prescribed, prophylactic treatment, and presence of inhibitors at baseline. Survival analysis methods were used to evaluate relationships between baseline risk factors and subsequent hospitalization rates. During 8708 person years (PYs) of follow‐up, 808 subjects (30.5%) had a total of 1847 bleeding‐related hospitalizations; an overall rate of 21.2 admissions per 100 PYs. Using proportional hazards regression to adjust for all of the studied factors, we found that home therapy use (among residents of four of the states) and care in HTCs were independently associated with a decreased risk for a first HBC. Patients who had government‐sponsored health insurance or who had no insurance, those of minority race or ethnicity, those with higher levels of factor use, and those with inhibitors were at increased HBC risk. We conclude that the use of home therapy and receipt of care in HTCs are each associated with a substantially lower risk for HBC among males with haemophilia.
Acquired haemophilia: experiences with a standardized approach
Authors: Grünewald M. , Beneke H. , GÜthner C. , Germowitz A. , Brommer A. , Griesshammer M.
Published: March 2003

Acquired haemophilia is a rare, life‐threatening, acquired bleeding diathesis. No general consensus exists on the best therapeutic approach. We report on the standardized approach at our institution evaluated in ten patients with acquired haemophilia. Factor VIII inhibitors were found in all patients, activities ranging from 1 to 648 Bethesda units (BU). Eight of the ten patients presented with severe bleeding. Two patients died during the acute phase, one from intracranial bleeding and one due to Mycoplasma pneumonia. One patient with mild bleeding was treated with immunosuppression alone. Two patients with factor VIII inhibitor activities below 5 BU were started on factor VIII concentrate therapy. Therapy was successful in one and was changed to recombinant human activated factor VII infusion (rFVIIa) in the other, owing to insufficient factor VIII recovery. Six patients with factor VIII inhibitor activities above 5 BU were started on activated prothrombin complex concentrate (APCC) therapy. APCC treatment was successful initially in all six patients and was changed to rFVIIa infusion in one for rebleeding. One patient did not receive any specific therapy. Immunosuppression with prednisolone (2 mg kg−1) was begun in nine patients and was continued with cyclophosphamide (2 mg kg−1) in six. A complete remission of the acquired haemophilia was found in seven of the eight patients surviving the acute phase, one had a partial remission. All patients with acquired haemophilia could be managed effectively following our standardized approach. Routine administration of immunosuppression was associated with high inhibitor elimination rates.
Recombinant factor IX (BeneFix®) by adjusted continuous infusion: a study of stability, sterility and clinical experience
Authors: Chowdary P. , Dasani H. , Jones J. A. H. , Loran C. M. , Eldridge A. , Hughes S. , Collins P. W.
Published: March 2003

The safety and efficacy of adjusted continuous infusion (CI) of recombinant factor IX (FIX; BeneFix®) was assessed in vitro and in a clinical study. BeneFix® was reconstituted at 100 IU mL−1 with or without unfractionated heparin (4 U mL−1) and stored at either 4 °C or room temperature. Reconstituted BeneFix® retained at least 90% activity over 14 days if stored at 4 °C but stability was reduced at room temperature. BeneFix® reconstituted in a sterile pharmacy was free of bacterial contamination. Six patients with haemophilia B received seven CIs of BeneFix® to cover routine surgery and severe bleeding episodes. The CIs lasted between 3 and 10 days. In all cases, haemostasis was excellent and the desired therapeutic FIX level was easily maintained. No thrombotic episodes or inhibitor development occurred but two patients developed thrombophlebitis at the infusion site when heparin was not added to the infusion. BeneFix® is not currently licensed for CI and we suggest that studies to enable licensing should be established as soon as possible.
Validity of health status measurement with the Dutch Arthritis Impact Measurement Scale 2 in individuals with severe haemophilia
Authors: De Joode E. W. P. , Van Meeteren N. L. U. , Van Den Berg H. M. , De Kleijn P. , Helders P. J. M.
Published: March 2003

The aim of this study was to investigate the validity of the Dutch Arthritis Impact Measurement Scales 2 (D‐AIMS2). Hence, D‐AIMS2 data of individuals with severe haemophilia were correlated with clinical and perceived health‐related quality of life data. Patients with severe haemophilia, who visit the Van Creveldkliniek on a regular basis, were administered the D‐AIMS2. In addition, health‐related quality of life was measured by the Sickness Impact Profile (SIP). As clinical indices, range of movement (which was converted into Joint Alignment and Motion scores) and muscle strength were recorded during the routine visit. Extensive descriptive and correlational (linear) analyses between corresponding datasets were performed. Thirty‐one individuals with severe haemophilia were included. Their scores on the D‐AIMS2 demonstrated moderate to very high internal consistency for scales and components (Cronbach’s α=0.62–0.92). The physical health components of the D‐AIMS2 and the SIP were significantly correlated (Pearson’s r=0.53; P < 0.05). The psychological health and social interaction components of the D‐AIMS2 did not correlate significantly with the psychosocial component of the SIP. The physical health component of the D‐AIMS2 correlated significantly with the clinical data for the lower extremities (r=0.52 and r =−0.45; P < 0.05). These data support the reliability and validity of the physical aspects of the D‐AIMS2 in patients with severe haemophilia. The next step should be to extend the investigation of psychometric qualities of this health‐related questionnaire in a larger population.
Factor VIII gene inversions and polymorphisms in Brazilian patients with haemophilia A: carrier detection and prenatal diagnosis
Authors: Soares R. P. S. , Chamone D. A. F. , Bydlowski S. P.
Published: March 2003

In families afflicted with haemophilia A, genetic counselling is often requested. Inversion mutations and polymorphic sites of the FVIII gene have been examined in a Brazilian population, with the aim of developing a strategy that would be accurate and informative for carrier analysis and prenatal diagnosis in Brazil. Patients with haemophilia A and families were studied. Inversion mutations in the FVIII gene were detected in 39.4% of severely affected patients, 85% of them being of distal type. No inversions were observed in patients with mild or moderate forms of the disease. Two bi‐allelic polymorphisms were studied. Intron 18 SSCP and intron 19 RFLP analyses indicated the presence of a restriction site in 39.5% and 42.9% of haemophilics, respectively. Two multiallelic microsatellite polymorphisms in introns 13 and 22 were also studied; eight different alleles were detected in each system with a heterozygosity rate of 83.08% and 78.77%, respectively. When all four intragenic loci were examined in linkage analysis, the cumulative reliability was 100%. In conclusion, inversion mutation analysis should be the first‐line test for Brazilian patients with severe haemophilia A. In cases of severe haemophilia A where no inversion could be detected or in mild or moderate haemophilia A, the use of all four polymorphisms is very informative for linkage analysis and should be used for carrier detection and genetic counselling in the Brazilian population.
Intraleucocyte platelet‐activating factor levels in desmopressin‐treated patients with haemophilia A and von Willebrand disease
Authors: Kavakli K. , Hüseyinov A. , Çoker I. , Aydinok Y. , Nisli G.
Published: March 2003

Despite the intensive clinical use of 1‐deamino‐8‐D‐arginine vasopressin (desmopressin; DDAVP) for 20 years, its mechanism of action is still not completely explained. It has been proposed that DDAVP stimulates release of a ‘second messenger’ which in turn stimulates release of von Willebrand factor (vWF) from endothelial cells. Platelet‐activating factor (PAF) and interleukin (IL)‐6 were individually proposed to be mediators for haemostatic action. The aim of this study was to investigate cellular‐based PAF levels in patients with haemophilia A (HA) and von Willebrand disease (vWD) before and after DDAVP treatment and also to look for any probable relationship between the haemostatic response of DDAVP and cellular PAF activities. In total, 20 patients (11 HA and nine vWD) were enrolled in the study. DDAVP was given subcutaneously as a single dose (0.3 μg kg–1). Ten patients responded to DDAVP and were defined as the ‘able group’ (four mild HA, six type 1 vWD). The remaining 10 patients did not respond to DDAVP and were defined as the ‘unable group’ (seven severe HA, three type 3 vWD). Released (extracellular) and intracellular (intraleucocyte) PAF levels under the stimulation of specific agents (A23187 and Zymosan) were measured by high‐performance liquid chromatography and radioimmunoassay. Extracellular and intracellular PAF activities were not detected without stimulation in healthy children whereas significantly higher PAF levels were found in the patients (extracellular: 37.5 ± 34.4 ng per 107 cells; intracellular: 24.8 ± 23.5 ng per 107 cells; P=0.0001). Intracellular PAF levels obtained from in vitro unstimulated cells were significantly higher in DDAVP‐responsive (able) patients in comparison to DDAVP‐unresponsive (unable) patients (52.1 ± 18.5 vs. 28.9 ± 8.0 ng per 107cells). After in vitro stimulation by A23187, intracellular PAF activities were significantly higher in patients than in controls (209.3 ± 26.1 vs. 172 ± 18.1 ng per 107 cells). Intracellular PAF levels obtained from in vitro stimulated cells by A23187 were also significantly higher in the ‘able’ patients in comparison to the ‘unable’ patients (277 ± 43.5 vs. 225 ± 30 ng per 107cells). In conclusion, cellular PAF activities are significantly higher in patients with HA and vWD. We also suggest that PAF, especially intracellular PAF mediates intracellular signalling and may be one of the important mediators for the haemostatic response of DDAVP.
Hepatitis C viral clearance and antibody reactivity patterns in persons with haemophilia and other congenital bleeding disorders
Authors: Messick K. , Sanders J. C. , Goedert J. J. , Eyster M. E.
Published: March 2003

We studied hepatitis C virus (HCV) clearance and antibody reactivity patterns in a cohort of 100 haemophiliacs exposed to unsterilized blood products, of whom 25 were antiHCV negative and 75 were antiHCV positive [49 human immunodeficiency virus (HIV) negative and 26 HIV positive]. HCV RNA was measured by the 2.0 bDNA assay and an ‘in‐house’ polymerase chain reaction assay. Antibody reactivity patterns were examined using a recombinant immunoblot assay (RIBA). Prior HCV infection was found in two (8%) of 25 antiHCV negative patients. HCV viraemia persisted in all 26 antiHCV+ patients who were coinfected with HIV. HCV RNA clearance was found in 12 (25%) of 49 antiHCV+, HIV− patients. Viral clearance was associated with younger current age (P < 0.01) and age at infection (P < 0.001), but not with duration of infection or with dose or frequency of clotting factor use. RIBA ratios reflecting an index of each patient’s overall reactivity to four HCV epitopes were significantly lower in those with viral clearance (P < 0.0001). Over a period of 15 years, those with viral clearance demonstrated significant loss of reactivity to the NS3, NS4 and NS5 epitopes, while those with viral persistence demonstrated relatively stable reactivities to all epitopes. We conclude that spontaneous HCV RNA clearance in haemophiliacs is age‐related and is unlikely to occur in those coinfected with HIV. The loss of antibody reactivity for some epitopes, especially c22 (core), may be a marker for the natural resolution of chronic HCV infection.
Health‐related quality‐of‐life treatments for severe haemophilia: utility measurements using the Standard Gamble technique
Authors: NARAINE V. S. , RISEBROUGH N. A. , OH P. , BLANCHETTE V. S. , LEE S. , STAIN A‐M. , HEDDEN D. , TEITEL J. M. , FELDMAN B. M.
Published: March 2003

Prophylaxis for haemophilia improves outcomes, but at a substantial cost. Cost–utility analysis balances improvements seen in health‐related quality of life (HRQoL) against costs, with the purpose of aiding healthcare decision‐making. This analysis uses a measure of HRQoL known as utility. The objective of this study was to measure HRQoL (utility) values for states of health that result from on‐demand therapy or prophylaxis. The HRQoL for different health states (including target joint bleeding, different intensities of prophylaxis, and indwelling intravenous catheters [ports]) was measured for healthy adults (n=30), parents of haemophilic children (n=30), and adults with haemophilia (n=28). Parents and patients rated health states similarly. Healthy adults gave the lowest ratings. The following rank, in order of HRQoL, was obtained: prophylaxis (low > medium > high) > on‐demand therapy > prophylaxis with port> prophylaxis with infected port > on‐demand therapy with development of a target joint. We conclude that: (1) haemophilia and its treatment reduce HRQoL; (2) prophylaxis is preferred to on‐demand therapy; (3) intravenous ports substantially reduce HRQoL; (4) and an intravenous port to provide prophylaxis is preferable to on‐demand therapy if a target joint develops.
Evaluation of outcome of care in patients with haemophilia
Authors: BEETON K.
Published: March 2003

Haemophilia is a potentially disabling condition associated with high financial costs, and so the need for robust measures to evaluate outcome of care is essential. This paper is a review of some of the outcome measures commonly used to evaluate treatment in haemophilia and includes quality of life measures, evaluation of the musculoskeletal system and orthopaedic surgical procedures. Quality‐of‐life questionnaires are discussed with particular reference to the SF36 and AIMS2. Results of published studies to date have demonstrated variable results. Overall, haemophilia appears to reduce quality of life compared to normal population figures. Several factors are perceived to reduce quality of life, and these include being human immunodeficiency virus (HIV) positive, having impairments, and a history of orthopaedic surgery. The evaluation of the musculoskeletal system is important in order to detect any deterioration over time. Various standardized measurement tools are described. Orthopaedic surgical procedures have also been evaluated in patients with haemophilia. To date, the Hospital for Special Surgery Knee rating scale has been the most commonly used to evaluate the outcome of total knee replacement. The limitations of this system for patients with haemophilia are outlined. Overall, these measures provide useful tools for evaluating outcome, but none have been specifically developed for patients with haemophilia. Further studies would be useful to evaluate these tools and others in more depth.
Risk of variant Creuzfeldt–Jakob disease from factor concentrates: current perspectives
Authors: FARRUGIA A.
Published: March 2003

The demonstration of iatrogenic transmission of Creuzfeldt–Jakob disease (CJD) through therapeutic interventions led to substantial concerns in communities requiring blood products in the 1980s and 1990s. These concerns led some regulatory authorities to adopt a very precautionary approach and require recall of plasma products, including factor concentrates, which included donors at risk of CJD. The FDA's approach on recall contributed to a substantial lack of plasma products on the world market in the mid‐ to late 1990s. Growing epidemiological evidence of non‐transmission of CJD to humans through blood, as well as demonstration of the plasma fractionation system's ability to eliminate CJD‐type agents, led the FDA to rescind its measures for product recall in 1998.

Although no evidence exists that the variant strain of CJD (vCJD) will behave any differently to the classic strain (cCJD) of the disease during fractionation, indications that higher levels of the strain may be present in the blood in vCJD, as well as the uncertainty regarding the epidemiology of the disease, has led to a new round of precautionary measures aimed at minimizing vCJD risk. Currently, the traditional approach to product safety through appropriate donor selection, screening using laboratory tests and systematic pathogen elimination is not completely possible for addressing the risk of vCJD. The only definite risk factor for vCJD is residence in a country where meat products from cattle with bovine spongiform encephalopathy (BSE) have been consumed; currently this is predominantly the United Kingdom but the appearance of BSE in other European countries has stimulated non‐European regulatory authorities to defer blood donors from most of Europe. There is currently no screening test available for vCJD. Plasma fractionation techniques fortuitously appear to eliminate substantial amounts of vCJD like agents but only one pathogen eliminating technique, nanofiltration, has been proposed for specifically eliminating vCJD‐like agents.

Despite the current uncertainty, it is possible to be cautiously optimistic regarding the safety of factor concentrates from the risk of vCJD. An accumulating body of evidence suggests that it is unlikely that the plasma pool from countries with moderate BSE epidemics will contain sufficient levels of vCJD agent to lead to an infective final product. Nevertheless, the development of a blood screening test and more dedicated elimination methods are high priorities for the blood industry as it faces this new threat. The community of blood product users, including people with haemophilia, need to be in a position to make an informed choice regarding the risk of this new agent. Such a choice needs to take into account the alternatives to plasma product therapy such as recombinant concentrates and the risks to product supply ensuing from an excessive reliance on one form of product.
The natural history and antiviral treatment of hepatitis C in haemophilia
Authors: LEE C. , DUSHEIKO G.
Published: March 2003

People with haemophilia who received non‐virucidally treated large‐pool clotting factor before 1986 were infected with hepatitis C virus (HCV), previously referred to as non‐A, non‐B hepatitis. Approximately one‐tenth of patients have been shown to clear infection naturally and shown persistently negative HCV PCR. Patients have been infected with genotypes 1, 2 and 3 reflecting the plasma donors in Northern Europe and the United States. Several studies have shown that HCV mono‐infection has a very slow progression. Co‐infection with human immunodeficiency virus (HIV), however, can hasten the progression to cirrhosis and liver failure. Genotype 1 and older age at first infection also increase the progression rate. Candidates with detectable HCV RNA are candidates for therapy. The combination of standard interferon‐alpha and ribavirin doubles the effectiveness of interferon‐alpha alone and is the current standard of care for the treatment of chronic hepatitis C. The duration of therapy depends on the genotype and level of viraemia. Patients with genotypes 2 or 3 should have 6 months' therapy while those with genotype 1 and > 2 million copies mL−1 should have 1 year of therapy. Pegylated interferon is an emerging therapy. Patients co‐infected with HIV, in whom treatment has stabilized the HIV infection, may be able to tolerate therapy for HCV infection. Liver transplantation is indicated for patients with haemophilia who have decompensated hepatitis C infection.
Orphan drugs: legal aspects, current situation
Authors: Lavandeira A.
Published: March 2003

Summary.  ‘Rare disorders’ is the name given to those diseases, of very varied aetiology, whose common denominator is that they are low‐prevalence diseases, and for the majority of which there is no treatment available. The World Health Organization defines a rare disorder as all pathological conditions affecting 0.65–1 out of every 1000 inhabitants. The European Union understands a rare disorder to be one with a prevalence of 5 : 10 000 Europeans; the USA defines it as an ailment affecting fewer than 200 000 Americans; Japan sets the limit at 50 000 Japanese patients; Australia at 2000 Australian patients. According to the aforementioned ratios, haemophilia, von Willebrand disease and other congenital coagulation disorders could be considered to be rare disorders. ‘Orphan drugs’ is the term given to those drugs intended for the treatment of rare disorders, because the number of patients affected is so small that it is not profitable to invest in research and development or to market them. Although the ratio of people affected by haemophilia means it could be classed as a rare disorder and its treatment could therefore be given orphan designation, haemophilia does have an established treatment, and research and development in this area proves profitable for the pharmaceutical companies. Haemophilia is therefore singular in that pharmaceutical companies can file an application for orphan designation with all the benefits deriving from this, while the treatment of haemophilia is profitable in its own right for companies carrying out research and development for the products involved.
Breastfeeding does not influence the development of inhibitors in haemophilia
Authors: Knobe K. E. , Tengborn L. I. , Petrini P. , Ljung R. C. R.
Published: March 2003

Summary.  Our aim was to test the hypothesis that breastfeeding may reduce development of inhibitors in male infants with haemophilia by inducing an oral immune tolerance to factor VIII. To achieve that goal, we performed a structured epidemiological survey comprising all males born with severe haemophilia A (in all 100 patients, 19 with inhibitors) or haemophilia B (in all 16 patients, six with inhibitors) in Sweden in 1980–99. Our results show no protective effect of breastfeeding.
Interferon and ribavirin in HIV‐negative haemophiliacs with chronic hepatitis C who were nonresponders to a previous interferon treatment
Authors: Franchini M. , Tagliaferri A. , Rossetti G. , Capra F. , Veneri D. , De Maria E. , Pattacini C. , Aprili G. , Gandini G.
Published: March 2003

Summary. Between January 1999 and December 2001, 33 HIV‐negative haemophiliacs with interferon‐nonresponsive chronic hepatitis C were treated with interferon (IFN) α2b (5 MU three times weekly) and ribavirin (1–1.2 g daily) for 12 months. Four patients (12.1%) dropped out of the study due to adverse effects. At the end of therapy, normalization of ALT occurred in 14/33 treated patients (42.4%) and HCV‐RNA was cleared in 12 (36.4%). Eleven patients (33.3%) became sustained responders. Genotype 1 was the only factor associated with a poor response to therapy (P < 0.001). Our study shows that IFN and ribavirin combination therapy is effective in HIV‐negative chronically HCV‐infected haemophiliacs who do not respond to a previous IFN treatment.
Prophylactic versus on‐demand treatment strategies for severe haemophilia: a comparison of costs and long‐term outcome
Authors: Fischer K. , Van der Bom J. G. , Molho P. , Negrier C. , Mauser‐Bunschoten E. P. , Roosendaal G. , De Kleijn P. , Grobbee D. E. , Van Den Berg H. M.
Published: March 2003

Summary.  A multicentre study was performed to compare clotting factor use and outcome between on‐demand and prophylactic treatment strategies for patients with severe haemophilia. Data on treatment and outcome of 49 Dutch patients with severe haemophilia, born 1970–80, primarily treated with prophylaxis, were compared with those of 106 French patients, who were primarily treated on demand. Dutch patients received intermediate dose prophylaxis, for a median duration of 12.7 years. Patients primarily treated with prophylaxis had fewer joint bleeds per year (median 2.8 vs. 11.5), a higher proportion of patients without joint bleeds (29% vs. 9%), lower clinical scores (median 2.0 vs. 8.0), and less arthropathy as measured by the Pettersson score (median 7 points vs. 16 points). Mean annual clotting factor use was equal at 1488 ± 783 IU kg−1 year−1 (mean ± standard deviation) for patients primarily treated with prophylaxis and 1612 ± 1442 IU kg−1 year−1 for patients primarily treated on demand. These findings suggest that, compared with a primarily on‐demand treatment strategy, a primarily prophylactic treatment strategy leads to better outcome at equal treatment costs in young adults with severe haemophilia.
Inhibitor development and FVIII gene mutation analysis in a pediatric cohort treated with sucrose formulated, full‐length recombinant Factor VIII
Authors: Kreuz W. , Leissinger C , Oldenburg J , Lusher J , Kelleher J , Gorina E , Kellermann E , Larson P ,   the International rFVIII‐FS Study Group
Published: March 2003

Treatment of previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe hemophilia A using FVIII concentrates is complicated by FVIII inhibitor formation in ∼30% of patients. The incidence of FVIII inhibitors was determined in a prospective clinical trial of sucrose‐formulated full‐length recombinant FVIII (rFVIII‐FS, KOGENATE® Bayer; Kogenate® FS) in pediatric patients.

Methods:  PUPs and MTPs (=4 exposure days‐EDs) with hemophilia A (<2% FVIII) were enrolled from 19 EU and 13 US centers. Sixty patients were evaluable for inhibitor formation (EU, 31; US, 29). Patients were tested regularly with the Nijmegen‐modified Bethesda assay (negative, ≤0.6 BU; Low Titer, >0.6‐5 BU; High Titer, >5 BU).

Results:  In the EU cohort (31 Caucasian), 4 patients developed inhibitors (3 Low; 1 High). Five high titer inhibitors developed in the US cohort (17 Caucasian; 5 Black; 7 Other). Median EDs at inhibitor detection was 8 [range, 3‐16], and at study end 1 EU and 4 US patients had <20 EDs. The incidence of inhibitors in patients achieving 20 ED was 16.4% (9/55).

Conclusions:  The rate of inhibitor formation in pediatric patients with severe hemophilia A treated with rFVIII‐FS is consistent with that observed with plasma‐derived and other recombinant FVIII products. Major gene disruptions were observed in all inhibitor patients.
Value of magnetic resonance imaging for the diagnosis and follow‐up of haemophilic arthropathy
Authors: Dobón M. , Lucía J. F. , Aguilar C. , Mayayo E. , Roca M. , Solano V. , Peña A. , Giralt M. , Ferrández A.
Published: March 2003

Summary. An orthopaedic assessment of the joint status of seven severe haemophiliacs (mean age 12.5 y – range 8.9–15.5) on prophylactic treatment (PT) by magnetic resonance imaging (MRI) and physical examination was carried out. Median duration of PT of these patients was 84 months (range 32–107). A locally designed MRI joint score considering seven parameters (1 – joint effusion,2 – synovial membrane thickening, 3 – haemosiderin deposits, 4 – joint cartilage injury, 5 – subchondral bone erosion, 6 – subchondral bone cysts,7 – osteonecrosis) was used (maximum score = 13 points). MRI scans were performed in 17 joints (nine ankles, seven knees and one elbow): mean MRI scores for the affected joints was 5.1. A poor consistency between physical examination and MRI findings or the real extent of joint damage was found (Cohen kappa index 0.320). MRI is a precise non‐invasive tool for the assessment of early joint cartilage and synovium pathological changes still undetectable by physical examination or conventional X‐rays in the haemophilic setting.
Promoting safer sex among HIV‐positive youth with haemophilia: theory, intervention, and outcome
Authors: Butler R. B. , Schultz J. R. , Forsberg A. D. , Brown L. K. , Parsons J. T. , King G. , Kocik S. M. , Jarvis D. , Schulz S. L. , Manco‐Johnson M. ,   the CDC Adolescent HBIEP Study Group
Published: March 2003

Summary.  The goal of the project was to develop and evaluate theory‐based interventions designed to change sexual behaviour and promote safer sex practices of HIV seropositive young men and adolescents with haemophilia to prevent transmission to sexual partners and offspring. Safer sex was defined as abstinence, consistent condom use, or ‘outercourse’ (intimate, non‐intercourse sexual behaviour). This project utilized the Transtheoretical Model developed by Prochaska and DiClemente, which describes behaviour change as an incremental, stage‐based process. The 1‐year intervention protocol consisted of two individual sessions and two peer‐centred activities. One hundred and four adolescents, residing in 22 states, participated. Pre‐ and post‐intervention evaluations were conducted to measure stage progression for participants. The number who were in the action or maintenance stage of change for safer sex was significantly greater at post‐test than at pre‐test (79 vs. 62%, P < 0.0001). Participants also reported an increased use of outercourse. In addition, significant increases in self‐efficacy and knowledge regarding safer sex were demonstrated. Following these stage‐based interventions, participants were significantly more likely to be engaging in safer sex behaviours than they were previously. These intervention activities can be adapted for use with other adolescent populations and for other behaviour change goals in adolescents with haemophilia.
Canopy phenology of some mopane and miombo woodlands in eastern Zambia
Authors: Fuller Douglas O.
Published: March 2003

Measurements of tree canopy closure and field‐layer reflectance were made in a series of plots in protected areas of eastern Zambia as part of a multiyear study of savanna woodlands. The plots were located in the Luangwa Valley and adjacent plateaux, which contained a range of vegetation types found in southern Africa. The vegetation consisted of four broad types: 1.plateau miombo woodland; 2.valley miombo woodland; 3.scrub miombo woodland; and 4.scrub and woodland mopane. Hemispherical photographs of the tree layer provided measurements of tree canopy phenology in the different vegetation plots. The most seasonal woodland type was mopane, where tree canopy closure ranged from about 15% at the end of the dry season to just over 60% during the peak of the rains. Plateau miombo exhibited the lowest range of seasonality in the tree layer, ranging from about 40% to 60% closure over one complete seasonal cycle. Phenology of the field layer, expressed as the normalized difference vegetation index (NDVI), closely followed that of the tree layer, although the field layer senesced earlier than trees, especially in plots with relatively low tree canopy closure. The relationship between tree‐canopy closure and field‐layer NDVI was positive and statistically significant for all sites of the study area, which suggests that woody biomass and herbaceous biomass are related positively in these savanna woodland ecosystems.
Scale, succession and complexity in island biogeography: are we asking the right questions?
Authors: Whittaker Robert J.
Published: March 2003

This paper offers a commentary on the development of island ecological theory since the publication of MacArthur & Wilson’s equilibrium theory in the 1960s. I distinguish the simple model at the core of their Equilibrium Theory of Island Biogeography (ETIB) and the broader body of their theory, which embraces evolutionary as well as ecological patterns — all, however, within the overarching framework or assumption of equilibrium.

The basic problems with the ETIB have long been known, and its status as a ruling paradigm has been the subject of concern for more than two decades. With the development of nonequilibrium ideas in ecology, island biogeographers arguably now have viable theoretical frameworks to set alongside or around the ETIB. Four conditions are highlighted as extremes: i) dynamic equilibrium; ii) dynamic nonequilibrium; iii) ‘static’ equilibrium; and iv) ‘static’ nonequilibrium: together providing a conceptual framework for island ecological analyses.

The importance of scale is stressed and attention is drawn to Haila’s spatial‐temporal continuum as an organizational device. It is argued that the processes represented within the ETIB (and by extension, other island theories) may be prominent within only a limited portion of this continuum, while elsewhere they are generally subsumed by other dominant processes.

Colonization and ecosystem development of near‐shore islands constitute just a special case of ecological succession, and thus the development of theories of island assembly may benefit accordingly from efforts to incorporate ideas from the ecological succession literature.

The desirability of specifying answerable questions is stressed, as is the need to build a greater degree of complexity into the development of island ecological models. Notwithstanding which, it is also recognized that key advances are often brought about by simple, but bold models, of the form exemplified elsewhere in this issue.
Atypical nasal challenges in patients with idiopathic rhinitis: more evidence for the existence of allergy in the absence of atopy?
Authors: S. Carney A. , Powe D. G. , Huskisson R. S. , Jones N. S.
Published: March 2003

Background The pathophysiology of idiopathic rhinitis is unknown although evidence is accumulating to suggest that many patients may have a localized form of allergic rhinitis in the absence of other atopic symptoms and markers. This study compares detailed nasal challenge results obtained from patients with idiopathic rhinitis to those of atopic and normal controls.

Methods Patients with idiopathic rhinitis (n = 23), perennial allergic rhinitis (n = 8) and normal controls (n = 8) underwent a normal saline challenge to exclude hyper‐reactivity and then bilateral nasal allergen challenges. Nasal patency was assessed by anterior active rhinomanometry.

Results All of the patients with atopic rhinitis demonstrated positive bilateral allergen challenges. All normal control subjects had bilateral negative challenges. Two patients in the idiopathic group tested positively to saline and were excluded from further study with 62% of the remainder testing positive to allergens. Of the idiopathic patients testing positive, 85% were sensitive to house dust mite.

Conclusion A significant proportion of patients with idiopathic rhinitis have positive nasal challenges, the vast majority to house dust mite allergen. These findings add to the weight of evidence that suggests ‘localized allergy’ may exist in the absence of systemic atopic markers.
The involvement of matrix metalloproteinases in basement membrane injury in a murine model of acute allergic airway inflammation
Authors: Kumagai K. , Ohno I. , Imai K. , Nawata J. , Hayashi K. , Okada S. , Senoo H. , Hattori T. , Shirato K.
Published: March 2003

Background Airway remodelling in asthma such as subepithelial fibrosis is thought to be the repair process that follows the continuing injury as of chronic airway inflammation. However, how acute allergic inflammation causes tissue injury in the epithelial basement membrane in asthmatic airways remains unclear. Matrix metalloproteinases (MMPs) capable of degrading almost all of the extracellular matrix components have been demonstrated to be involved in cell migration through the basement membrane in vivo and in vitro.

Objective We investigated the alterations of matrix construction and the role of MMPs in matrix degradation in the subepithelium during acute allergic airway inflammation.

Methods Airway inflammation, the ultrastructure of the subepithelium and injury of types III and IV collagen in tracheal tissues from ovalbumin (OVA)‐sensitized mice after OVA inhalation with or without the administration of tissue inhibitor of metalloproteinase‐2 (TIMP‐2) and dexamethasone were evaluated by cell counting in bronchoalveolar lavage (BAL) fluids, electron microscopy and immunohistochemistry, respectively.

Results The disruption of the lamina densa and matrix construction and the decrease of the immunoreactivity for type IV collagen in subepithelium were observed in association with the accumulation of inflammatory cells in airways 3 days after OVA inhalation. This disorganization of the matrix components in the subepithelium, as well the cellular accumulation, was abolished by the administration of TIMP‐2 and dexamethasone. The immunoreactivity for type IV collagen in the subepithelium in OVA‐inhaled mice returned to the level of that in saline‐inhaled mice 10 days after inhalation in association with a decrease of the cell numbers in the BAL fluid. The immunoreactivity for type III collagen was changed neither 3 nor 10 days after OVA inhalation.

Conclusion These results suggest that epithelial basement membrane gets injured by, at least in part, MMPs as a consequence of cell transmigration through the membrane during acute allergic airway inflammation.