bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective, randomized, double‐blind controlled trial of laparoscopic uterine nerve ablation in the treatment of pelvic pain associated with endometriosis
Authors: Sutton Christopher , Pooley Andrew S. , Jones Kevin D. , Dover Richard W. , Haines Patricia
Published: March 2003

To determine the value of laparoscopic uterine nerve ablation (LUNA) as part of the laparoscopic laser treatment of painful endometriosis.

A prospective randomized double‐blind controlled trial.

A referral centre for the treatment of endometriosis.

51 women with pelvic pain and pelvic endometriosis.

All patients underwent laparoscopic laser ablation of their endometriosis and were then randomly allocated to receive LUNA or no further treatment.

Dysmenorrhoea, dyspareunia and chronic non‐menstrual pelvic pain were assessed using visual analogue scales and structured questionnaires, preoperatively and at 3 and 6 months postoperatively.

24 patients were randomly allocated to receive laser vaporization alone, and 27 to receive a LUNA procedure in addition. The mean age of the patients involved was 28 years (range 20–41), with no differences between the groups for stage of endometriosis. Comparisons were made between the two treatment groups at 3 and 6 months. Significant differences in favour of the non‐LUNA group were found at 3 months (P = 0.003), and at 6 months (P = 0.022) for dysmenorrhoea. A significant difference in favour of the non‐LUNA group also occurred at 6 months for chronic non‐menstrual pain (P = 0.323). There were no significant differences recorded for dyspareunia. Bonferroni's adjustment was applied, and the only difference which remained significant was for dysmenorrhoea at 3 months (P = 0.033) in favour of the non‐LUNA group. The preoperative and 6‐month pain scores for all the patients were combined. There was a significant improvement in the pain scores recorded at 6 months (P < 0.0001).

Laparoscopic laser ablation of endometriosis is confirmed as an effective treatment, to which uterine nerve ablation adds no benefit.
What research should be done in gynaecological endoscopy? A national questionnaire survey of members of the British Society of Gynaecological Endoscopy
Authors: Clark T. Justin , Mahajan Deepa , Sunder Ponnamal , Bingham Tracy , Khan Khalid S. , Gupta Janesh K.
Published: March 2003

To determine current research activity and establish views on the direction of future research in gynaecological endoscopy.

A self‐administered structured questionnaire was posted to 389 UK gynaecologists to enquire about current research activity and collect their views on future research within gynaecological endoscopy.

Members of the British Society of Gynaecological Endoscopy (BSGE).

The postal questionnaire was returned by 100 BSGE members (26% response rate) and of these respondents, 47 (47%) were actively involved in research. The majority of respondents (99/100, 99%), believed that the BSGE should play a proactive role in directing future research in gynaecological endoscopy. Therapeutic laparoscopy was the area of gynaecological endoscopy identified most frequently (80/100, 80%) for future study. Within this area, 22/80 (28%) specified the need for studies into laparoscopic treatment of endometriosis, especially comparative studies between ablative and excisional treatment (15/22, 68%).

There is a substantial commitment to research in gynaecological endoscopy by BSGE members who responded to the survey. The BSGE should play a proactive role in defining its research remit in health technology assessment. Future research requiring priority should focus on determining the effectiveness of laparoscopic methods of treatment for endometriosis.
Is laparoscopic surgery really worth it? The views of patients, hospital doctors and health care managers
Authors: Hart Roger , Ruach Meir , Magos Adam
Published: March 2003

To determine the relative benefits of minimal access surgery (MAS) as perceived by patients and health care professionals.

Prospective descriptive study (design classification III).

A large undergraduate teaching hospital in the North Thames Region.

100 patients (50 gynaecological, 50 antenatal), 70 obstetricians and gynaecologists, and 30 senior hospital managers.

A specially designed questionnaire was used which included 44 pairs of clinical scenarios for laparotomy and laparoscopy. Each scenario consisted of different permutations of four of the variables, incision size, operating time, major complication rate, hospital stay and recovery time. Respondents were asked to select their preferred route of surgery. They also ranked, in order of priority, the above five variables together with treatment cost.

MAS was preferred by the majority. Most patients chose endoscopy even if the operating time was four times longer and there was no reduction in hospitalization, and 25% accepted a quadrupling of the major complication rate. A minority of surgeons chose laparoscopy if the operating time exceeded 2 h or the risk of a major complication was increased fourfold. Most respondents preferred MAS, even if recovery time was equal to that of laparotomy. All respondents ranked complication rate as the main priority and cost as the least. Overall, patients were significantly more in favour of MAS than were surgeons, and the views of managers were in between the views of these two groups.

Both health care professionals and patients, especially the latter, prefer MAS to conventional surgery, even if the operating time is longer and the major complication rate is higher.
A longitudinal study of immunological status in Chinese Haemophiliacs: importance of the heat viral inactivation of factor concentrates. II. Improvements of CD4/CD8 ratio after treatments with heat‐inactivated factor concentrates
Authors: Shen Ming‐Ching , Hu Fu‐Chang , Lin Jen‐Shiou , Tsai Way , Fon Mei‐Fua , Wang En‐Chi
Published: March 2003

Screened and heated clotting factor concentrates of intermediate purity have been used in Taiwanese Haemophiliacs since the end of 1986. A significant improvement of CD4/CD8 ratio during the years 1987–1989 as compared with those during the years 1984–1986 was observed in Haemophilia A patients [mean±SD (median), 1.191±0.495 (1.163) vs. 0.880±0.325 (0.838), P=0.0020] who were seronegative for human immunodeficiency virus. Almost all patients received an increased amount of factor VIII concentrates and total plasma products since 1987. Multiple linear regression analysis for the association of CD4/CD8 ratio with changes in dosage of plasma products revealed that there was a significant positive association of CD4/CD8 ratio measured during 1987–1989 with dosage of factor VIII concentrate administered during 1984–1986 (P=0.0230), which is an indicator for changes in viral load, but not with changes in dosage of plasma products, which are indicators for changes in plasma protein intake. Our data indicate that immunological abnormalities after replacement therapy observed in Haemophiliacs are mainly attributed to virus infection through infusion of factor concentrates, not to allogeneic proteins existing in plasma products.
Multidose pharmacokinetics of factor IX: implications for dosing in prophylaxis
Authors: CarLsson  , BjÖrkMan  , BerNtorp
Published: March 2003

The aim of this study was to investigate the use of single‐dose pharmacokinetic data for factor IX (FIX) to predict multidose pharmacokinetics and explore their use for pharmacokinetic dosing in prophylactic treatment of Haemophilia B. Eight patients with severe Haemophilia B were enrolled. Using single‐dose pharmacokinetic data for each patient, plasma factor IX procoagulant activity (FIX:C) curves during prophylactic dosing were computer‐simulated. The simulations were verified by repeated blood sampling and measurements of FIX:C. Theoretical dosing regimens to maintain a plasma trough level of 1.0 U dL−1 of FIX:C were calculated. A 2 × 2 week cross‐over study on standard dosing according to bodyweight vs. dosing every three days based on individual pharmacokinetics was carried out. FIX:C was measured during each treatment period. FIX:C data from the plasma sampling generally confirmed the single‐dose pharmacokinetic data used. Pharmacokinetically tailored dosing of FIX could result in considerable savings of factor concentrate as compared to current standard dosing. The study demonstrates the applicability of individual pharmacokinetics as a tool for cost‐effective utilization of FIX concentrates in the prophylactic treatment of Haemophilia B.
Laboratory performance of haemophilia centres in developing countries: 3 years’ experience of the World Federation of Hemophilia External Quality Assessment Scheme
Authors: Jennings I. , Kitchen S. , Woods T. A. L. , Preston F. E.
Published: March 2003

A World Federation of Hemophilia External Quality Assessment Scheme has been established to promote high standards of laboratory performance in haemophilia centres worldwide. Results from 21 International Haemophilia Training Centres (IHTCs) provide target values for the prothrombin time (PT), activated partial thromboplastin time (APTT), factor VIII:C, IX:C and von Willebrand factor (VWF) assays, against which the performance of Haemophilia Centres in developing countries (HCs) can be assessed.

Eight surveys were distributed over a 3‐year period between 1994 and 1997. A higher proportion of HCs failed to identify an abnormal PT or APTT in samples from donors with mild deficiencies of the extrinsic and intrinsic systems, respectively. For factor VIII:C and IX:C assays, agreement between HC results was consistently poorer than between IHTCs. However, improvement in between‐centre agreement could be seen for two samples distributed on more than one occasion. A minority of HCs perform assays for VWF, and a questionnaire revealed equipment and reagent costs as limiting the range of assays which could be carried out in several centres. However, agreement was in some cases better between those HCs that did perform VWF assays than between IHTCs. The problems of screening test sensitivity and between‐centre agreement for factor assays need to be addressed, together with the limitations which prevent HCs from performing a full range of tests in the diagnosis and treatment of bleeding disorders.
Carrier testing and prenatal diagnosis of haemophilia — utilisation and psychological consequences
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , TEDGÅRD U.
Published: March 2003

Summary. Attitudes towards prenatal diagnosis, and abortion vary widely between different countries, religions, cultures and over time. Carrier testing and prenatal diagnosis (PD) of haemophilia have become an integrated part of the comprehensive care for haemophilia in Sweden as well as in many other countries. Almost all carriers are interested in carrier testing if they are aware of the possibility. With the development of PD by chorionic villus sampling in the first trimester, the method became acceptable for many carriers, and it has in Sweden actually had an effect on the incidence of haemophilia in the 1990s. The use of PD is more common among women who perceive haemophilia as a very serious disease and who have a positive attitude towards legal abortion. The main reason for carriers not to use PD was that they do not find haemophilia to be a sufficiently serious disorder to justify an abortion. Women and their spouses are under a great deal of psychological pressure in association with the PD procedure, and the psychological consequences of having to terminate a pregnancy are long‐lasting. At follow‐up, about 6 years after PD and abortion, these women, however, do not have more signs of psychological distress than women without PD experience. Nevertheless, they must be offered qualified assistance both before and after PD as well as adequate follow‐up after an abortion to help them cope with the emotional strain they are under.
Control of the synovium in haemophilia
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , EICKHOFF H. H. , RADERSCHADT G. , KOCH W. , BRACKMANN H.‐H.
Published: March 2003

Summary. Adequate factor substitution is a prerequisite for successful conservative or operative treatment of haemophilic synovitis. Subsequent prophylactic factor substitution can prevent further joint problems in the future. Orthopaedic treatment regimes are dependent on the classification of the synovitis and the stage of the arthropathy. Synovitis can be classified into acute and chronic forms. The arthropathy is classified according to Arnold and Hilgartner. When the synovitis has already become chronic, early arthroscopic synovectomy is recommended in order to prevent the otherwise inexorable progress of the arthropathy. Failure to treat in the early phase of the pathology causes problems in the correction of further stages. The progression of the joint disease can be shown both clincally and radiologically as the arthropathy develops, and influences the treatment.
Factor VIII inhibitors in mild and moderate‐severity haemophilia A
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , HAY C. R. M.
Published: March 2003

Summary. Inhibitors are an uncommon complication of mild haemophilia, occurring in 3–13% of patients and usually arising during adulthood. The risk of inhibitor development in this group appears to be associated with relatively few high‐risk factor VIII genotypes clustered in the A2 and C2 domains, especially the Arg593‐Cys and the Trp2229‐Cys mutations. Kindreds with these mutations have an inhibitor incidence of up to 40%. These mutations may induce a stable conformational change in the factor VIII molecule rendering it antigenically distinct from wild‐type factor VIII. Inhibitors in mild haemophilia usually cross‐react with endogenous factor VIII reducing the basal VIIIC to <0.01 IU/ml, and causing spontaneous bleeding. This bleeding is sometimes severe and life‐threatening, two‐thirds of patients developing a pattern of soft tissue, gastrointestinal (GI) and urinogenital bleeding reminiscent of acquired haemophilia. Bleeding has been treated with human and porcine factor VIII, bypass therapy and DDAVP. Recombinant factor VIIa and DDAVP have the advantage that they do not induce an anamnestic rise in inhibitor titre. About 60% of these inhibitors disappear in the remainder over a median of 9 months. Few of these inhibitors recur, suggesting that most such patients have become tolerant. The inhibitors persist long‐term and remain troublesome in about 40% of patients. The limited data available on immune tolerance induction in this group indicate a generally poor response to this approach. Two of nine achieved tolerance, with a partial response in a further four. Inhibitors are an uncommon but life‐threatening complication of haemophilia. This complication should be considered when selecting the treatment modality for patients with a family history of inhibitors, and DDAVP used whenever possible.
Vaccines for prevention of viral hepatitis
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , SHOUVAL D.
Published: March 2003

Summary. At the end of the 20th century active immunization against hepatitis A and B has been introduced into routine medical practice. Therefore, patients at risk, and especially those with coagulation disorders, should be immunized at the earliest age possible. In contrast, development of an efficacious vaccine against hepatitis C remains an important goal for the next decade.
Recombinant factor VIIa versus aPCCs in haemophiliacs with inhibitors: treatment and cost considerations
Authors: Teitel
Published: March 2003

For haemophiliacs with factor VIII inhibitor titres greater than approximately 5 Bethesda Units, haemostasis is best achieved with activated prothrombin complex concentrates (aPCCs, AUTOPLEX®T and FEIBA®) and the recently approved recombinant factor VIIa (rFVIIa). The optimal treatment should be determined by consideration of efficacy, safety, availability, cost and convenience. The current evidence does not allow definitive conclusions to be drawn regarding the relative efficacy of aPCCs and rFVIIa. The principal safety concerns are transmission of viral or other pathogens, thrombogenicity and immunogenicity. The two aPCCs are derived from human plasma and therefore carry the potential for transmitting viruses. This risk is negligible for rFVIIa, although this product could theoretically transmit animal pathogens. The aPCCs are clinically safe in most applications. Likewise, rFVIIa should be considered potentially thrombogenic, though with a low risk. The aPCCs contain detectable factor VIII and can therefore be immunogenic, but in practice this rarely affects their efficacy. The costs of single doses of aPCCs and rFVIIa are similar, but a treatment course of rFVIIa typically requires more doses. Treatment with rFVIIa may be more cumbersome owing to the requirement for more frequent administration. In addition, as for any product for which there is only a single supplier, availability could be vulnerable in some circumstances.
Assessment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders
Authors: KADIR  , ECONOMIDES  , SABIN  , POLLARD  , LEE
Published: March 2003

Menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders were assessed in this study. One hundred and sixteen women, including 66 with von Willebrand's disease (vWD), 30 carriers of haemophilia and 20 with factor XI (FXI) deficiency were interviewed and their gynaecological history obtained. Their case records were also reviewed and menstrual loss was objectively assessed using a pictorial blood assessment chart (PBAC). Comparison with an age‐matched control group (69 women) was performed. Menorrhagia (PBAC score>  100) was confirmed in 74%, 57% and 59% of women with vWD, carriers of haemophilia and FXI deficiency, respectively, in comparison with 29% in the control group (P = 0.001). PBAC scores were higher in vWD patients with a von Willebrand factor activity (vWF:Ac) of ≤ 30 IU dL−1 compared to those with higher levels, but the difference was not statistically significant. However, there was no relation between PBAC score and the severity of the disease in FXI deficient patients and carriers of haemophilia. Duration of menstruation was significantly longer (P = 0.001) and episodes of flooding was significantly more common (P = 0.001) in patients with inherited bleeding disorders compared to the control group. However, there was no difference in the passage of clots during menstruation. Forty‐seven per cent of patients with inherited bleeding disorders had consultations with their family practitioner or gynaecologist for menorrhagia, 36% had medical treatment and 27% had surgical procedures, including 10 hysterectomies. Post‐operative bleeding followed in four out of 28 cases of hysteroscopy and/or dilatation and curettage. Bleeding complications following hysterectomy were reported in five out of 10 patients. In conclusion, menorrhagia is a common and major problem in patients with inherited bleeding disorders, especially vWD. Increased awareness among gynaecologists and haematologists of the high prevalence of menorrhagia and the treatment options available is necessary for optimal management of these patients. Appropriate preoperative assessment and haemostatic control during any gynaecological procedure, however minor, and in collaboration with the local haemophilia centre is essential to minimize risks of haemorrhagic complications.
Spinal epidural haematoma in haemophilia A with inhibitors – efficacy of recombinant factor VIIa concentrate
Authors: Leach  , Makris  , Hampton  , Preston
Published: March 2003

We report the case of a 21‐year‐old man with severe haemophilia A and factor VIII inhibitors who presented with an extensive spinal epidural haematoma (C2‐T12), probably induced by sit‐up exercises. The bleed was defined by magnetic resonance imaging of the cervical and thoracic spine and prompt treatment with recombinant factor VIIa concentrate led to complete resolution at 4 weeks. Neurological sequelae were averted and surgical decompression was not necessary. We discuss the difficulties in diagnosis and management of such a case.
Desmopressin in the treatment of women’s bleeding disorders
Authors: Lethagen
Published: March 2003

Bleeding disorders in women are an underestimated problem that deserves increased attention. About 9%–14% of females have menorrhagia and, amongst them, there is a significant over‐representation of von Willebrand disease (VWD), with a prevalence of 13% in this group as compared with about 1% in the general population. The bleeding disorder has not been diagnosed in most of these women and they may therefore be withheld from treatment with desmopressin, which is effective in most cases of VWD and also in platelet dysfunctions and mild factor VIII deficiency. This paper is a review of the haemostatic use of desmopressin with special reference to women’s bleeding disorders, the mechanisms of action, modes of administration, clinical indications, dosage recommendations, and hospital or home treatment. Desmopressin stimulates endogenous release of FVIII and von Willebrand factor (VWF), it increases platelet adhesiveness and shortens bleeding time. It can be given as intravenous or subcutaneous injection, but the intranasal spray is probably the most practical mode of administration for females with bleeding disorders as it is simple to administer and suitable for home treatment. The spray has been used successfully in connection with menorrhagia and other bleeding symptoms.
Haemophilia B carrier detection by factor IX:C analysis; no impact of the type of mutation or severity of disorder
Authors: Knobe  , Ljung
Published: March 2003

Haemophilia B, an X‐linked recessive bleeding disorder characterized by lack or deficiency of factor IX, has been shown to be caused by any of a variety of DNA abnormalities (partial or total deletions, nonsense or missense mutations). Since in most countries carrier detection is based on factor IX coagulant activity (FIX:C) assay, this study was designed to determine whether carriers’ FIX:C values are dependent on the severity of haemophilia (mild, moderate or severe) or on the genetic anomaly in the family. FIX:C concentrations were studied in 28 obligate carriers, 39 women known to carry the mutation and 33 verified noncarriers subgrouped by severity of disorder or genetic anomaly. No significant subgroup differences in FIX:C values were found, thus suggesting the level of FIX:C concentrations in carriers to be unaffected by the severity of haemophilia, or by its expression (i.e. deficient or dysfunctional factor IX). The specificity and sensitivity of FIX:C analysis for the purpose of carrier diagnosis was judged by receiver operating characteristic curve analysis, where an FIX:C cut‐off level of 75 IU dL–1 was found to be optimal (sensitivity 93% and specificity 88%).
Extensor supracondylar femoral osteotomy as treatment for flexed haemophilic knee
Authors: Caviglia H.A. , Perez‐Bianco R. , Galatro G. , Duhalde C. , Tezanos‐Pinto M.
Published: March 2003

The experience with extensor supracondylar femoral osteotomy as treatment for the flexed haemophilic knee is presented with the description of 19 patients treated during a 30‐year period (1968–98).The average age of the patients was 16 (8–35 years), and the average age follow‐up was 13 years (3–30 years). Six patients had flexion fixed deformity while the rest presented 40° average range of motion (10–75°). In 13 patients a single osteotomy without internal fixation was performed, in one an osteosynthesis with a condylar plate and in five stabilization was achieved by means of Blount staples. Previous surgery was performed in two patients with patello‐femoral ankylosis. The osteotomy site was consolidated in every patient and the deformity was corrected. Two bleeding complications were observed: one haemarthrosis and one psoas haematoma.

Flexion relapsed in one patient who underwent another procedure after 12 years. One patient presented with a peroneal nerve paralysis; another one a genu recurvartum; which required flexor osteotomy.

The extensor supracondylar femoral osteotomy is a procedure that aligns the limb with scarce modification of articular mobility.
Diagnosis of two related carriers of severe haemophilia B with no family history
Authors: Lorenzo J. I. , Casaña P. , Espinós C. , Ferrer R. , Aznar J. A.
Published: March 2003

Haemophilia B is an X‐linked disease affecting 1 in 30 000 males. Carrier diagnosis is usually carried out only in female relatives of haemophilic males, and the likelihood of discovering a carrier without a haemophilic male is very low. In this report we present the cases of two related women without a family history of haemophilia who were diagnosed as haemophilia B carriers. Following a minor haemorrhage in the proband, she and her mother were thought to be haemophilia B carriers because of a low factor IX level (16 and 23 IU dL–1, respectively; normal values >50 IU dL–1). The non‐sense mutation C31118T, which is associated with severe haemophilia B, was detected in both women. This allowed us to diagnose them as being definite carriers of severe haemophilia B and give appropriate genetic counselling.
Recombinant FVIIa (NovoSeven) continuous infusion and total hip replacement in patients with haemophilia and high titre of inhibitors to FVIII: experience of two cases
Authors: Tagariello  , De Biasi  , Gajo  , Risato  , Radossi  , Davoli  , Traldi
Published: March 2003

In this report we describe our experience of total hip replacement in two patients with severe haemophilia A and high titres of inhibitors to FVIII. We used rFVIIa replacement therapy by continuous infusion to perform the surgery. The total amount of rFVIIa used in these two patients was very similar but the manner of administration was quite different. In our experience, it is an advantage to use a higher dose for shorter periods than a lower dose for a longer treatment period. Tranexamic acid by continuous infusion, and parallel saline infusion were useful for good haemostasis and avoided local thrombophlebitis in the side of rFVIIa infusion.
Late clinical, plain X‐ray and magnetic resonance imaging findings in haemophilic joints treated with radiosynoviorthesis
Authors: Nuss R. , Kilcoyne R. F. , Rivard G.‐E. , Murphy J.
Published: March 2003

The clinical, plain X‐ray and magnetic resonance imaging (MRI) findings were studied in 13 haemophilic joints previously treated with radiosynoviorthesis. 32P had been injected into the joints at a median of 16 years earlier in an attempt to halt recurrent haemorrhage. Prior to 32P injection, the majority of joints demonstrated bone damage evident on plain X‐ray, secondary to recurrent haemorrhage. At the follow‐up evaluation we found plain X‐rays were adequate to identify cysts, erosions and cartilage loss in these very damaged joints. MRI was superior to clinical examination and plain X‐ray in identifying synovial hyperplasia and effusions.
Gene therapy: a 2001 perspective
Authors: High K.A.
Published: March 2003

In the past year, three clinical trials of gene therapy for haemophilia have been initiated. Years of preclinical studies have culminated in translation of research findings into the clinical arena. It is too early to predict which, if any, of these strategies will show efficacy. This paper will review basic aspects of gene therapy for haemophilia and will briefly outline current clinical trials. The three clinical trials all share a dose escalation design. The ongoing trial for haemophilia B involves the intramuscular administration of an adeno‐associated virus (AAV) vector expressing human factor IX. In preclinical studies, this strategy has produced therapeutic levels of circulating factor IX in haemophilic mice and dogs.
General principles and indications of synoviorthesis (medical synovectomy) in haemophilia
Authors: Rodriguez‐Merchan E.C. , Wiedel J.D.
Published: March 2003

The indication for a synoviorthesis (medical synovectomy) is chronic haemophilic synovitis causing recurrent haemarthroses, unresponsive to haematological treatment. Synoviorthesis is the intra‐articular injection of a certain material to diminish the degree of synovial hypertrophy, decreasing the number and frequency of haemarthroses. There are two basic types of synoviorthesis: chemical synoviorthesis and radiation synoviorthesis. On average, the efficacy of the procedure ranges from 76 to 80%, and can be performed at any age. The procedure slows the cartilaginous damage which intra‐articular blood tends to produce in the long term. Synoviorthesis can be repeated up to three times with 3‐month intervals if radioactive materials are used (Yttrium‐90 and Phosphorus‐32), or weekly up to 10–15 times if rifampicin (chemical synovectomy) is used. After 30 years of using radiation synovectomy worldwide, no damage has been reported in relation to the radioactive materials. Radiation synovectomy is currently the preferred procedure when radioactive materials are available, however, rifampicin is an effective alternative method if radioactive materials are not available. Several joints can be injected in a single session, although no more than two joints at the same time is probably the best protocol to follow.
Synoviorthesis with radioactive Yttrium in haemophilia: Israel experience
Authors: Heim M. , Goshen E. , Amit Y. , Martinowitz U.
Published: March 2003

Radioactive Yttrium‐90 (90Y) was injected into 163 joints. Of these patients 115 were persons with haemophilia and they suffered from recurrent haemarthroses. The median age at the time of the initial exposure to90Y was between 11 and 15 years and the median follow‐up period 11 years. Over 80% of the patients with haemophilia reported a decrease in the number of haemarthroses and 15% stopped bleeding altogether in the treated articulation. The safety of this modality of management has been reported and hence the patients age should not be regarded as a criteria.
32P chromic phosphate radiosynovectomy for chronic haemophilic synovitis
Authors: Silva M. , Luck J.R. , Siegel M.E.
Published: March 2003

The principal medical consequence of haemophilia is the development of arthropathy, initiated by a haemarthrosis giving rise to chronic synovitis. Traditional methods of synovectomy include open excision and arthroscopy each of which require substantial amounts of clotting factor concentrate for several weeks, and in the case of open synovectomy, is often associated with loss of range of motion and arthrofibrosis. Radiosynovectomy, the intra‐articular injection of low penetration radiocolloids, has been utilized outside the United States for over 20 years. Since 1988, our centre has performed 170 radiosynovectomies utilizing32P chromic phosphate (32P). This study reports results of 13032P radiosyovectomies with an average follow‐up of 36.5 months (6–140 months). For primary procedures, excellent and good results (haemarthrosis reduction from 75 to 100%) were obtained in 79.2% of cases at 6 months to 8 years. For repeat procedures a combination of excellent and good results were obtained in 62.4% of cases at 6 months to 3 years. Regression analysis showed no correlation between results and age or degree of arthropathy. Radiation was well contained within the joint. There were no observed or identified complications. The procedure is highly cost effective in comparison to open surgical or arthroscopic synovectomy.
Acquired haemophilia in association with organ‐specific autoimmune disease
Authors: Meiklejohn D. J. , Watson H. G.
Published: March 2003

A 72‐year‐old woman presented with multiple sites of soft tissue bleeding and a left ulnar neuropathy due to a compartment syndrome. There were also clinical signs of hypothyroidism. Factor VIII:C (FVIII) levels were 6% and a FVIII inhibitor with a titre of 9 Bethesda units was detected. She had biochemical evidence of hypothyroidism and high titres of antithyroid antibodies were detected. Two episodes of life‐ or limb‐threatening haemorrhage were successfully treated with FEIBA. The inhibitor disappeared following 2 months of immunosuppression with oral cyclophosphamide and corticosteroids. She then developed autoimmune haemolytic anaemia, which responded to further immunosuppression with oral prednisolone. The association between acquired haemophilia and systemic autoimmune disorders such as systemic lupus erythematosis is well recognized, but our description of an association with organ‐specific autoimmunity is more unusual.
Pain status of patients with severe haemophilic arthropathy
Authors: Wallny T. , Hess L. , Seuser A. , Zander D. , Brackmann H. H. , Kraft C. N.
Published: March 2003

Patients with severe haemophilia A growing up before the establishment of prophylactic treatment frequently developed significant haemarthropathies. The goal of the following study was to clarify the role of haemarthropathic pain for haemophilic patients. Furthermore, we aimed to determine to what degree daily activities are influenced by the impairment and which therapeutic modalities are used in pain management. Using a questionnaire we consulted 71 haemophiliacs concerning their complaints and how they were treated in 1999 (average age 43 years; range 21–63 years). The pain in the large joints and spine and the effect of specific treatment was estimated by a visual analogue scale. On average, there were four joints with major pain and 0.5 with minor pain. The most frequent sources of pain were the ankle joints (45%), followed by the knee (39%), spine (14%) and elbow (7%). Fifty percent of all patients complained of pain throughout the day if no treatment was applied. In 29% of patients, pain persisted after application of factor VIII (FVIII), while 12% claimed that pain still remained after use of FVIII and painkillers. Restriction in activities of daily life was reported by 89% of the group and 85% reported on an impact of pain on their mood. Patients primarily used FVIII to decrease pain, followed in frequency by use of anti‐inflammatory drugs, orthopaedic footwear, liniments and bandages. Haemophilic patients with haemarthropathy are chronic pain patients. By means of the questionnaire, it is possible to reveal the ‘silent’ sufferers. Sufficient pain treatment is essential so as to increase the patient’s quality of life and avoid inadvertent abnormal postures possibly resulting in increased loading of joints and subsequent bleeding episodes.
Soft‐tissue angioleiomyoma of the hand as a rare differential diagnosis of haemophilic pseudotumour
Authors: Gassel F. , Kraft C. N. , Wallny T. , Hess L. , Schmitt O.
Published: March 2003

The benign vascular tumours known as angioleiomyomas, which originate from smooth muscle cells of arterial or venous walls are rare, particularly in the region of the hand. Frequently, the diagnosis is only made after surgical extirpation and histological assessment. The occurrence of an angioleiomyoma in a haemophiliac has not yet been reported, to our knowledge. A 62‐year‐old patient with a haemophilia B complained of increasing pain in the vicinity of the soft tissue covering the carpo‐metacarpophalangeal joint of his left palm. In the T1‐weighted magnetic resonance images a hypointense well‐demarcated mass was found, showing a homogenous enhancement after intravenous application of contrast medium. T2‐weighted images showed a hyperintense signal. Based on clinical and radiographic findings, the tumour was initially thought to be a haemophilic pseudotumour arising from a prior local haematoma. Intraoperatively, the mass was found to be solid, and histological assessment diagnosed an angioleiomyoma, without signs of malignant transformation. Descriptions of the clinical symptoms of angioleiomyoma in an extremity vary considerably in the literature. Alhough rare, the vascular leiomyoma should therefore be contemplated in the differential diagnosis in patients with a solid nodular lesion of unclear aetiology in arms or legs. Especially in a haemophiliac patient, the growth can easily be mistaken for a pseudotumour because of its clinical and radiological similarities.
Haemorrhage in upper cervical cord: an unusual manifestation in moderate haemophilia patients who ride motorbikes
Authors: Ghosh K. , Shetty S. , Mohanty D.
Published: March 2003

A young asymptomatic patient, with moderate haemophilia due to factor IX deficiency, developed symptoms of upper cord compression caused by a haemorrhage 12 hours after riding a motorcycle on a poorly maintained road. This led to quadriparesis with respiratory paralysis. In spite of neurosurgical intervention and intensive management with respirator therapy, the patient died 13 days after the incident from pneumonia and multi‐organ failure. This is a very rare presentation of moderate haemophilia with serious consequences and has not to our knowledge, previously been reported in the English literature.
Gene therapy for haemophilia: the end of a ‘royal pathology’ in the third millennium?
Authors: Liras A.
Published: March 2003

Haemophilia is an ideal condition for gene therapy because of its monogenetic character and the fact that it requires only a small amount of the expressed protein to achieve palliation. To date, research in the field of gene therapy for haemophilia has largely relied on retroviruses, adenoviruses and adeno‐associated viruses as transfer vectors and the major aims will be to achieve stable longlasting in vivo expression of factors VIII or IX (FVIII or FIX) at therapeutic levels. Two clinical trials have been approved by the US Food and Drug Administration (FDA), using miniadenovirus FVIII and the intrahepatic and intramuscular delivery of adeno‐associated virus FIX. In the third millennium, haemophilia treatment should encompass more ambitious goals through gene replacement, to result in permanent and safe haemophilia ‘eradication’, making haemophilia a part of the history of medicine.
Complications of central venous catheters in patients with haemophilia and inhibitors
Authors: Morado M. , Jimenez‐Yuste V. , Villar A. , Quintana M. , Del Castillo F. , Garzon G. , Acitores I. , Ibañez F. , Sanjurjo M. J. , Gago J. , Hernandez‐Navarro F.
Published: March 2003

We report our clinical experience with central venous catheters (CVCs) in 15 patients with haemophilia who, in total, had 34 catheters inserted. Eighteen devices were Hickman, six were Port‐A‐Cath and 10 were nontunnelled catheters (one Quinton, seven antecubital, one jugular and one subclavian vein access). All patients had factor VIII/IX inhibitors at the time of insertion. The mean age at operation was 8.8 years (range 16 months–39 years). Eight of the 15 patients (26/34 implanted catheters, 76%) presented some kind of complication. Pericatheter bleeding during the postoperative period affected a total of seven CVCs (7/34, 20%) in six patients, which required substitutive treatment for several days. Infection was reported in 15 of the CVCs (15/34, 44%), and four of these (4/15, 26%) had more than one episode, with a mean of 1.4 infection episodes per catheter (21/15). The infection rate was 0.2 infections per 1000 patient days or 0.1 per 1000 catheter days. Despite the usefulness of CVCs in haemophilic patients, the high incidence of complications requires careful assessment of the type of device as well as continuous surveillance.
Factor VIII and transmissible spongiform encephalopathy: the case for safety
Authors: CERVENAKOVA L. , BROWN P. , HAMMOND D. J. , LEE C. A. , SAENKO E. L.
Published: March 2003

Haemophilia A is the most common inherited bleeding disorder, caused by a deficiency in coagulation factor VIII (FVIII). Current treatment of haemophilia A is based on repeated infusions of plasma‐derived FVIII concentrate or of recombinant FVIII, which may be exposed to plasma‐derived material of human or animal origin used in its tissue culture production process. We review epidemiological and experimental studies relevant to blood infectivity in the transmissible spongiform encephalopathies (TSEs, or `prion' diseases), and evaluate the hypothetical risk of TSE transmission through treatment with plasma‐derived or recombinant FVIII.
Paediatric care of the child with haemophilia
Authors: LJUNG R.
Published: March 2003

The paediatric care of children with haemophilia in developed countries should focus on the health of the child, not on the disorder. Gene therapy offers the hope of an ultimate `cure' for the disorder, but until this is a viable proposition, patients should be given more control over their treatment, and the focus should be on `self‐monitored and self‐adjusted' prophylaxis. New instruments for measuring joint function and radiographic changes, and quality of life are valuable tools in improving the treatment of paediatric care for children with haemophilia.
Haemophilic pseudotumours of the limbs and their percutaneous treatment
Authors: Caviglia H. A. , FernÁndez‐Palazzi F. , Gilbert M. S.
Published: March 2003

Summary.  The percutaneous treatment of limb pseudotumours is a nonaggressive method of treating␣haemophilic pseudotumours. However, efforts should be directed to the prevention of such pseudotumours by ensuring that all patients receive adequate treatment of their bleeding episodes through education and the elimination of geographical or social barriers that prevent access to such treatment. Prevention of pseudotumours by means of early substitution treatment of muscular bleeding episodes is the best treatment.
Gene therapy: reality or myth for the global bleeding disorders community?
Authors: Kelley K. , Verma I. , Pierce G. F.
Published: March 2003

Summary.  In recent years, five different human gene therapy clinical studies have been initiated in the United States, covering a broad spectrum of gene transfer technologies. Both in vivo and ex vivo studies have been performed, and a variety of target organs/tissues have been studied. The results of this early human clinical research indicate that there is still much to be done before a safe and effective gene therapy procedure becomes commercially available, but there is strong evidence that the obstacles that remain will not prove insurmountable. Small increases in circulating clotting factor levels have been achieved in some patients without significant side‐effects, providing proof of the principle that gene therapy can provide a therapeutic benefit for patients with haemophilia. Still unclear is whether gene therapy, when it becomes available, will be accessible to the global haemophilia community. As seen with recombinant and other high purity factor concentrates, technological advances do not always lead to improvements in care for the majority of the world's haemophilia patients. In fact, advances in technology can potentially increase the gulf in care if newer processes displace existing manufacturing technologies. A modified vaccine production model should be considered to make gene therapy more widely available to those who presently have inadequate access to treatment.
Two patients with haemophilia and acute leukaemia
Authors: Zülfi̇kar B.
Published: March 2003

Summary.  Acute leukaemia is the commonest form of malignancy in childhood. The coincidental development of leukaemia in children or adults with haemophilia is extremely rare, although cases of leukaemia and other malignancies have been reported previously in HIV‐positive subjects. Of a total of 440 people with haemophilia registered with our society, two were diagnosed with acute leukaemia last year. The development of leukaemia in a subject with haemophilia has previously been reported from our country in 1985, but the negative HIV status of these recent cases is very interesting. The first caseinvolved a 14‐year‐old boy with moderate haemophilia A, who developed acute lymphoblastic leukaemia (ALL) [French–American–British (FAB) classification L2]. The second subject was a 16‐year‐old boy who had moderately severe haemophilia A with no previous family history, and developed acute nonlymphocytic (myelomonocytic) leukaemia (FAB‐M4). Both patients received conventional chemotherapyand thisreport discusses the potential problems in management of such cases, including diagnosis and administration of chemotherapy in subjects with a pre‐existing haemorrhagic disorder. Extensive cutaneous and mucosal bleeding, as well as bleeds in joints previously affected by haemarthrosis and alterations of haematological values were all initially suggestive of the development of inhibitors against factor VIII, but the appearance of blasts in the peripheral blood and bone marrow led to the definitive diagnosis. The risk of bleeding, due to the combination of both leukaemia and the consequences of the chemotherapy, was overcome by the administration of coagulation factor concentrates (daily initially followed by prophylactic doses after successful induction of remission in both patients). The young patient with ALL is now receiving the maintenance phase of the Children's Cancer Study Group 1961 protocol and is in the 15th month of follow‐up, without any complications. The other case relapsed in the seventh month, developing enterobacter sepsis, and died. An important lesson to be learnt from these cases is that the possible diagnosis of leukaemia should not be overlooked in a patient with haemophilia and severe haemorrhagic problems, if the first‐line differential diagnosis of inhibitor development against factor VIII (or IX) has been excluded.
Gene therapy ethics and haemophilia: an inevitable therapeutic future?
Authors: Dimichele D. , Miller F. G. , Fins J. J.
Published: March 2003

Summary.  Haemophilia was recognized early on as an ideal candidate for a gene transfer approach to therapy. In the past decade, gene transfer experimentation in the haemophilias has indeed played an integral role in furthering the science in the global field of gene therapy. However, these expectations have placed haemophilia gene transfer researchers under pressure to succeed in a scientific domain in which successes are infrequent and progress is necessarily slow. These same expectations have also fuelled the perception of gene therapy as the inevitable therapeutic goal for the youngest children with haemophilia. In this paper, we will discuss the ethical implications of this perception in light of anticipated benefits, acceptable risk, perceived consumer need and the unknown cost of this intervention. A framework for the future study and therapeutic implementation of gene transfer technology in this specific population is proposed. Public debate on this issue that includes the voices of the intended beneficiaries, especially the parents of the youngest children with haemophilia and the children themselves, is encouraged.
Biogeographic relationships of primates on South‐East Asian islands
Authors: Harcourt A. H.
Published: March 2003

The number of primate species and genera on thirty‐one south‐east Asian islands west of the Wallace Line, including Sulawesi, is highly significantly related to surface area of the islands, as expected, but the z value (slope) of each relationship is low (0.21 for species). No association exists between number of taxa and distance to nearest mainland, or to nearest larger island. Excluding the non‐Sunda Shelf islands only negligibly changes the relationships. A significant correlation exists between island size and median taxon's body mass, with taxa of 10 kg or more occurring on only the two largest islands. Hence, the primate community changes greatly with island size. The existence of several genera, but no congeners, on small islands, and a checkerboard distribution of the two nocturnal genera (Nycticebus and Tarsius), hints at interspecific competition as a cause of extinction. It is suggested that for comparative purposes, genera/area analyses might be more useful than species/area analyses, because genera are more taxonomically stable, perhaps more comparable across deeper taxa, and might be a better indication of degree of variability.