bluuebunny/crossref_metadata_2025 huggingface dataset:
Small‐bowel obstruction secondary to incarcerated trocar‐site hernia after laparoscopic hysterectomy: a diagnostic challenge
Authors: Fruchter Oren , Lissak Arie , Eyal Avraham , Hallak Moshe , Heinrich Avraham , Abramovici Haim
Published: March 2003

Objective

To report an unusual complication of total laparoscopic hysterectomy.

Setting

Gynaecology Department at Carmel Medical Centre, Haifa, Israel.

Subject and interventions

A 40‐year‐old woman underwent total laparoscopic hysterectomy and developed small‐bowel obstruction 3 days following the operation subsequent to incarcerated hernia through a 12‐mm laparoscopic trocar wound. The diagnosis was eventually made with the aid of abdominal computerized tomography.

Conclusion

All laparoscopic surgeons should be aware of this uncommon complication of operative laparoscopy, its clinical presentation, and the imaging modalities for its diagnosis.
Laparoscopically controlled transvaginal colpoceliotomy: a technique for extraction of enucleated fibroids
Authors: Barišić Dubravko , Orešković Slavko , Dijaković Aleksandar
Published: March 2003

Objective 

To demonstrate the technique of laparoscopically controlled classic transvaginal posterior colpoceliotomy as a procedure for extraction of laparoscopically enucleated fibroids.

Setting 

University‐based hospital.

Subjects 

19 consecutive patients who underwent laparoscopic enucleation of intramural fibroids.

Interventions and results 

Laparoscopic myomectomy and extraction of enucleated fibroid via laparoscopically controlled transvaginal posterior colpoceliotomy was successfully performed in all 19 patients without complication. During the follow‐up period of between 3 and 25 months neither subjective nor objective postoperative sequelae were observed.

Conclusions 

Laparoscopically controlled transvaginal posterior colpoceliotomy is a safe, efficient and inexpensive procedure for fibroid extraction.
Pelvic adhesions and pelvic pain: opinions on cause and effect relationship and when to surgically intervene
Authors: Diamond M. P. , Bieber E. ,   the Adhesions Study Group.
Published: March 2003

In the absence of definitive data, we sought to determine the consensus on the contribution of adhesions to pelvic pain.

Impressions about the role of adhesion location, extent, and severity of pelvic pain, were surveyed among 13 gynaecological surgeons. They were asked whether adhesions covering specific organs to a varying extent would be likely to cause pain significant enough to require pain medication, or to lead a woman to alter her normal activities, and when they would recommend surgery to reduce pelvic pain.

Women with dense vascular adhesions covering all of the uterus but not the bowel or adnexal structures were thought to have a 49 ± 9% likelihood of having pelvic pain; this fell to a 34 ± 7% and 18 ± 5% likelihood of pain if 60% or 20%, respectively, of the uterus was involved with adhesions. Similar observations were made for adhesions involving the posterior cul‐de‐sac and large bowel. However, adhesions involving the anterior cul‐de‐sac were thought to be less likely to cause pain. Women with total involvement of both tubes and ovaries with dense, vascular adhesions were thought to be 60 ± 9% likely to have pelvic pain; reduction in extent of adhesions to 50% or 25% reduced the prediction of pain to 38 ± 5% and 21 ± 3%, respectively. In contrast, filmy adhesions to both tubes and ovaries, were thought to cause pain in 46 ± 9%, 26 ± 5%, and 13 ± 3% of women, respectively, according to extent. Half the surgeons said they would recommend surgery for patients with pain and dense adhesions involving 15% of both tubes and ovaries; 10 recommended surgery if it was known that adhesions involved 100% of both ovaries and tubes. Surgeons were only slightly less likely to recommend surgery for pain relief for adhesions involving either both tubes or both ovaries or for pain associated with unilateral tubal and ovarian adhesions. For bilateral tube and ovary adhesions, surgery was equally likely to be recommended for relief of pain when adhesions were cohesive and dense; for adhesions which were filmy, surgery was less likely to be recommended. For dense adhesions involving 20%, 40%, 60%, and 80% of the uterine surface, surgery was recommended by 42%, 58%, 83% and 92% of surgeons, respectively. Posterior cul‐de‐sac involvement resulted in recommendation of surgery by 50%, 83%, 92%, and 100% of surgeons, respectively; however, for corresponding amounts of anterior cul‐de‐sac adhesions, surgery was recommended by only 17%, 33%, 67%, and 75% of surgeons.

(1) Adhesions are frequently considered to be a cause of pelvic pain; (2) the likelihood of discomfort is related to location, extent, and to a lesser degree, the severity of adhesions, and (3) adhesiolysis is thought to provide the potential for pain relief.
A death following hysteroscopic myomectomy
Authors: Katz Yeshayahu , Moscovici Roland , Prego George , Merzel Yosef , Kniznik Daniel , Lev Amiram
Published: March 2003

We report a fatal outcome using 1.5% glycine as distension/irrigation fluid for hysteroscopic myomectomy.

During general anaesthesia for transcervical endoscopic resection of myoma, a healthy 35‐year‐old woman developed severe pulmonary hyponatraemia and cerebral oedema, and was declared brain dead. Postmortem findings did not reveal pontine myelinolysis. Through the procedure, the net fluid absorption of 1.5% glycine was 1.6 L plus 1 L of maintenance intravenous Ringer’s lactate solution.

Regional anaesthesia is recommended for hysteroscopy, since general anaesthesia may mask neurologic signs, and meticulous attention should be paid to intraoperative fluid balance.
ThermaChoice balloon endometrial ablation for menorrhagia: failure to develop and sustain operating pressures may be related to an unrecognized endometrial cancer
Authors: Onyeka Benjamin A. , Arthur Ian D. , Wilcox Frank L.
Published: March 2003

Objective To report a case of unsuccessful balloon ablation therapy for menorrhagia in the presence of an unsuspected stage 1b endometrial cancer, in a 45‐year‐old woman with no known risk factor for endometrial cancer.

Results Balloon ablation therapy in this woman was abandoned because of failure to generate and sustain enough pressure to perform the procedure. Hysteroscopy was therefore carried out, and abnormal uterine anatomy, perforation and obvious pathology were excluded. Balloon leakage or perforation was ruled out by aspiration of all the infused fluid. Endometrial curettings obtained at the time of hysteroscopy showed endometrial cancer, and at a later date the patient underwent total abdominal hysterectomy with bilateral salpingo‐oöphorectomy. The histological investigation showed a stage 1b endometrial cancer. A previous hysteroscopy performed 21 months earlier had shown no abnormality and the curettings had been histologically normal.

Conclusions This case suggests that endometrial cancer with muscle invasion may result in compromised myometrial integrity, so that the level of pressure needed to carry out the ablation procedure cannot be generated and maintained.
Continuous infusion of factor IX concentrate to induce immune tolerance in two patients with Haemophilia B
Authors: Tengborn  , Berntorp
Published: March 2003

Two patients with Haemophilia B and high‐responding inhibitor to factor IX were subjected to immune tolerance induction according to the Malmö protocol, including high dosage of factor IX, cyclophosphamide and intravenous gammaglobulin. In one of the patients the treatment was preceded by extracorporeal protein A adsorption. Both patients had previously been subjected to immune tolerance induction without success and as an attempt to improve the tolerance induction regimen and lower cost, factor IX was given as continuous infusion, with a dose of around 300 units per kg body weight daily for 3 weeks. The inhibitor level declined in one of the patients but tolerance was not achieved. In the second patient the inhibitor level remained high. Despite the failure of the treatment in these two cases, we propose that the constant antigen load provided by the continuous infusion of modern, safe, purified factor IX concentrate may theoretically be of greater benefit in immune tolerance induction than the varying load resulting from intermittent infusions. Larger study materials are needed to show if this is so.
Surgery in Haemophilia: experience from a centre in India
Authors: Ghosh  , Jijina  , Pathare  , Mohanty
Published: March 2003

The present paper describes various kinds of surgery carried out with great success in 16 cases which included both severe and moderate Haemophilia patients with modest amounts of factor concentrates and antifibrinolytic drugs. This is very important in developing countries where factor concentrates are not easily available. In one patient Haemophilia was diagnosed only after surgery. None of the patients had inhibitor pre‐ or post‐operatively. One patient who was HIV positive underwent orchidectomy successfully with only 6000 IU of factor VIII concentrate.
Clinical guidelines for treating von Willebrand disease patients who are not candidates for DDAVP — a survey of European physicians
Authors: Lusher
Published: March 2003

While certain plasma‐derived factor VIII/von Willebrand factor (FVIII/vWF) concentrates have proven to be quite useful in preventing or controlling bleeding in persons with von Willebrand disease who are not candidates for DDAVP, most of the information concerning dosage and effectiveness has been anecdotal. Additionally, the laboratory tests used to quantify vWF (the vWF:RCoF assay and collagen binding assay) are not well standardized. Thus, the US Food and Drug Administration (FDA) has been reluctant to grant licensed indication for use of these products in von Willebrand disease.

This brief report describes a survey of non‐US physicians (from major centres) who are recognized experts in haemophilia and von Willebrand disease. Twenty‐four of 27 questionnaires were completed, returned and analysed. Products thought to be effective in von Willebrand disease included Haemate P®, Facteur von Willebrand®, Alphanate®, and the UK’s BPL ‘8Y’®. In calculating dosage to stop or prevent bleeding, most aim for a certain level of both FVIII and vWF:RCoF. Postoperatively, 16/24 respondents follow both of these laboratory tests once daily. Twenty‐two of 24 would follow FVIII levels once daily. It is noteworthy that FVIII assay results are generally the only test results readily available to guide the respondents’ clinical decisions.

For treatment of significant mucous membrane bleeding, respondents often individualize dosage and monitoring, depending on the type, location and extent of bleeding. Gastrointestinal bleeding is generally treated more aggressively. Patient monitoring varies between merely looking for cessation of bleeding, to a battery of laboratory tests, including haemoglobin and haematocrit. Seven out of 24 would monitor BT as well.

In addition to FVIII content, 22/24 respondents noted that they would find it helpful to have vWF:RCoF listed on the label, while 15/24 would like to know the vWF multimeric composition.
Pharmacokinetics of von Willebrand factor and factor VIII coagulant activity in patients with von Willebrand disease type 3 and type 2
Authors: Menache
Published: March 2003

Nine patients with von Willebrand disease type 3, six with type 2B, one with type 2A, and one patient with type 1/2N were infused with one dose of ≈50 or 100 IU ristocetin cofactor activity (RCoF) per kg body weight of von Willebrand factor (vWF) (Human), a product with a very low content of factor VIII (FVIII). Blood samples were collected over 96 h. The data for RCoF and vWF antigen (vWF:Ag) were fitted to a 1‐compartment model decay. The data for FVIII:C were fitted to a model with a linear time ‘synthesis’ term and a 1‐compartment decay. Results in von Willebrand disease type 3 patients (nine patients; 10 infusions) indicated a volume of distribution of 39.9 and 39.8 mL kg−1 for RCoF and vWF:Ag, respectively. The FVIII:C rate of synthesis was 6.4 U dL−1 h−1 (range: 4.4–8.8). The decay rates for FVIII:C, RCoF, and vWF:Ag were 0.041 (h−1) [t1/2: 16.9 h]; 0.061 (h−1) [t1/2: 11.3 h] and 0.006 (h−1) [t1/2: 12.4 h], respectively. In patients with von Willebrand disease type 2 (n = 8) the RCoF mean volume of distribution was 46 mL kg−1. The factor VIIIC mean rate of synthesis was 5.5 U dL−1h−1 and the decay rate 0.043 (h−1) [t1/2: 16.1 h]. The rate of decay for RCoF and vWF:Ag were 0.050 (h−1) [t1/2: 13.9 h] and 0.044 (h−1) [t1/2: 15.7 h], respectively.
Towards achieving global haemophilia care — World Federation of Hemophilia programmes
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , LEE C. A.
Published: March 2003

Summary. The overall purpose of the “Decade Plan” published in 1992 was to do everything possible to make effective treatment available to people with haemophilia throughout the world. In 1990 it was estimated that there were 350,000 individuals with haemophilia worldwide, with 80% or 280,000 without treatment. By the year 2020 this may have reached the figure 440,000, or the population of Jerusalem. Earlier this century Carroll Birch reported a series of 113 patients where 82 died before their 15th year, and only six survived beyond 40. Thus as Jones has pointed out for the developing world this is a paediatric problem for the WFH to face now. The examples described in this paper illustrating the WFH programmes and the committment of many people from the 88 member organisations worldwide as well as the doctors and scientists shows what can be done through cooperation. There is no doubt that these achievements are capitalising from the unique quality of WFH from the beginning, that is a membership which includes both those with haemophilia and their families, and those with an interest in treating haemophilia.
Resource utilisation in haemophiliacs treated in Europe: Results from the European Study on Socioeconomic Aspects of Haemophilia Care
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , SZUCS T. D. , ÖFFNER A. , KRONER B. , GIANGRANDE P. , BERNTORP E. , SCHRAMM* W. ,   European Socioeconomic Study Group
Published: March 2003

Summary. The objectives of our study was to answer the following questions: (1) What are the socioeconomic costs and benefits of different haemophilia treatment strategies? (2) Which savings can be achieved through a comprehensive care program? (3) How are haemophiliacs integrated into their social life? (4) What are the annual costs of treating haemophilia from a third party payer perspective? In this cross‐sectional study, 840 consecutive haemophiliacs attending 16 haemophiliac treatment centres in 10 European countries at were entered in the study. The following six parameters were analysed: sociodemographic patient data, the type of substitution (on demand or prophylaxis), transfusion‐transmitted diseases, the functional joint status, quality of life as well as the total costs of therapy. Three kinds of substitution modalities were distinguished: on demand therapy, pure and modified prophylaxis. The average number of medical visits, the average length of hospital stay, regular drug therapy and the average number of days off work per bleeding joint were recorded from the medical charts as a basis for the subsequent assessment of the costs of therapy. The total study sample comprised of 566 patients. Interestingly, statistically more significant (P= 0.0005) patients were unemployed in the on‐demand group (14%) than in the prophylaxis group (3.4%). There was a higher ratio of white collar workers in the on‐demand group as compared to the prophylaxis group and vice versa for blue collar workers. The distribution of blue collar workers, clerk, self‐employed persons, students and housemen were quite comparable between the patients of the on‐demand and prophylactic therapeutic regimen. The labor force participation rate was 55.2% in the patients in the on demand and 59.3% in the patients in the modified prophylactic group. The labor force participation rate across all patients was 56%. Patients on demand therapy used on average 38.3 (median: 12.5) units/kg/week as compared to 68.6 (median: 6) units/kg/ week in the prophylaxis group. The mean usage across all patients was 46.1 (median 19.7) units/kg/week. There were an average of 7.4 (median: 3) joint bleeds per patient across all patients during the 6‐month observation period. In the on‐demand group 8.8 (median: 5) joint bleeds were recorded versus 3.1 joint bleeds (median: 0) in the prophylactic group. This differences was statistically different (95% CI of difference: 4.33–7.07). Our data suggest that patients receiving prophylactic clotting factor therapy require less additional health care resources, mainly due to the reduction in the number of joint bleeds.
Synovium in haemophilic arthropathy
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , ROOSENDAAL G. , MAUSER‐BUNSCHOTEN E. P. , DE KLEIJN P. , HEIJNEN L. , HM BERG V. D. , VAN RINSUM A. C. , LAFEBER F. P. J. G. , BIJLSMA J. W. J.
Published: March 2003

Summary. Synovium is an essential component of the joint and plays a critical role in maintaining a balance between physiological processes and pathological changes in the joint. Recurrent intra‐articular bleeding as occur in haemophilia induce pathological synovial changes in the joint. From a certain point on, synovitis inevitably plays a major role in joint destruction, although in the early phase of haemophilic arthropathy its role may be secondary to cartilage damage as a result of the direct effects of blood on cartilage. The changed haemosiderotic, synovial tissue produces catabolic cytokines and enzymes harmful for cartilage.
Incidence and treatment of hepatitis C virus infection in children with haemophilia in Poland
Authors: Adamowicz‐Salach  , Pawelec  , Łoch  , Zdziebłowska‐Pawińska  , Brojer  , Walewska‐Zielecka  , Rokicka‐Milewska
Published: March 2003

In 80% of children with haemophilia treated in our department, screening tests showed the presence of antibodies against the hepatitis C virus (HCV). HCV RNA was detected in serum in 41% of cases. In 20% of cases there were periodic increases in the level of alanine aminotransferase (ALT) activity, and in these cases liver biopsy was performed after factor concentrate replacement. No haemorrhagic complications or pain complaints were reported either during the biopsy or immediately afterwards. In all cases histhopathological examination revealed chronic hepatitis type C – chronic mild hepatitis and chronic minimal hepatitis. Eight boys were treated with interferon (INF) alpha. In two cases this therapy was successful. No HCV RNA was detected in serum and transaminase activity was normal during the year following interferon treatment.
Immunosuppressive effects of factor IX products: an in vitro study
Authors: Grosset  , McGregor  , Samlowski  , Rodgers
Published: March 2003

The effects of a recombinant factor IX product (BeneFix), and of five plasma‐derived factor IX products, AlphaNine, Immunine, Konyne, Mononine and Replinine on in vitro peripheral blood mononuclear cell (PBMC) immune function were compared in a blinded study. We assessed the effects of these products on Con‐A‐induced lymphocyte proliferation and interleukin‐2 and interleukin‐10 secretion, expression of lymphocyte activation markers, and nitric oxide secretion by stimulated mouse peritoneal macrophages. At 1  mL–1 for 48 h, Konyne reduced Con‐A‐induced mitogenesis by 50% (P < 0.05); AlphaNine, Mononine and BeneFix had no effect. At 10 IU mL–1, Con‐A‐induced mi‐ togenesis was at control levels with Mononine and BeneFix, but was reduced to <15% (P < 0.05) with each of the other products. IL‐2 and IL‐10 secretion by Con‐A‐stimulated lymphocytes was also markedly depressed by all the products tested except Mononine and BeneFix. Dialysis of these products did not substantially affect these results. Flow cytometric analysis of lymphocyte activation markers following Con‐A stimulation showed that Konyne also decreased IL‐2 receptor α and β chain (CD25 and CD122) induction on PBMC. Konyne also inhibited nitric oxide secretion to levels <18% of controls. These results indicate that certain factor IX products, including some of purported higher purity, substantially depress in vitro immune function. The importance of these findings to in vivo immune function in haemophilia B patients remains to be established.
Hamstring release and posterior capsulotomy for fixed knee flexion contracture in haemophiliacs
Authors: Wallny T. , Eickhoff H.H. , Raderschadt G. , Brackmann H.‐H.
Published: March 2003

Between 1977 and 1981 hamstring release (n = 27) and posterior capsulotomy (n = 22) were performed on 27 haemophilic patients. The follow‐up of 19 patients is documented for at least 5 years after the operation. The mean age was 30 years (15–40 years), the mean follow‐up period was 12.5 years (5–20 years). Postoperatively 16 of 19 knee joints achieved immediate full extension, three patients showed 10° extension deficiency. In the long run the original good result could be demonstrated in just 11 patients. Using the Orthopedic Advisory Committee of the World Federation of Hemophilia (OAC) Scores there were three good, 12 satisfactory and four poor results. In minor forms of arthropathy a hamstring release with posterior capsulotomy is the only recommended operation. In severe forms we would actually recommend a combination with other procedures such as arthroscopic synovectomy or joint replacement.
Prevalence of human parvovirus B19 and TT virus in a group of young Haemophiliacs in South Africa
Authors: Rubinstein  , Karabus  , Smuts  , Kolia  , Van Rensburg
Published: March 2003

A well recognized hazard of transfusion with blood or blood products is the acquisition of a viral infection. Parvovirus B19 and transfusion transmitted virus (TTV) are two of several non‐enveloped viruses that may on rare occasions be present in coagulation factor concentrates. The prevalence of these viruses in the South African Haemophilia population has not previously been studied. Thirty‐nine Haemophiliac children were investigated for evidence of parvovirus and TTV infection. 26 boys with Haemophilia A had been treated with cryoprecipitate or intermediate purity factor VIII, and 13 boys with Haemophilia B had received prothrombin complex concentrates. All the plasma products were prepared from South African donors and were virally inactivated by heat or solvent/detergent since 1992. A control group of 32 children who had not been transfused were also studied. IgG antibodies to B19 were present in 29 of the 39 patients (74%), 18/26 (69%) with Haemophilia A and 12 of the 13 (85%) with Haemophilia B. None of the patients was IgM antibody positive but two children were PCR positive for B19 DNA. Of the control children, 47% had IgG antibodies to B19, but none were IgM antibody or B19 DNA positive. TTV viral DNA was found in 10.2% of patients and in 9% of the control group. The results indicate that our locally produced plasma products are not a significant source of TTV transmitted infection but may contribute to infection by B19 parvovirus.
Safety and efficacy of a new recombinant FVIII formulated with sucrose (rFVIII–FS) in patients with haemophilia A: a long‐term, multicentre clinical study in Japan
Authors: Yoshioka A. , Shima M. , Fukutake K. , Takamatsu J. , Shirahata A. ,   the KOGENATE FS STUDY GROUP
Published: March 2003

The recombinant full‐length FVIII product Kogenate® has been reformulated using sucrose (rFVIII–FS) instead of human serum albumin as a stabiliser in purification and formulation. The in vivo recovery, haemostatic efficacy, and safety of rFVIII–FS were investigated in 20 previously treated patients with severe or moderate haemophilia A for ≥ 24 weeks. In vivo recoveries of 73.5 ± 16.3%, 78.4 ± 16.1%, and 82.8 ± 23.9% after the initial infusion of 50 IU kg−1 rFVIII–FS and at weeks 12 and 24, respectively, showed no significant changes over time. A total of 1115 infusions (mean dose 24.1 ± 8.4 IU kg−1) were included in the analysis of haemostatic efficacy. One (80.5%) or two (8.2%) infusions achieved adequate haemostasis in 88.7% of all bleeding episodes, and haemostatic efficacy was judged ‘excellent’ or ‘good’ in 749 of 764 episodes (98.0%). The haemostatic efficacy was judged as ‘excellent’ or ‘good’ in 924 of 1115 (82.9%) infusions. Twenty‐one adverse events were observed in 12 patients in the total 1541 infusions included in the safety analysis. Causality with respect to rFVIII–FS could not be ruled out in three events in one HIV‐negative patient: elevated CD4(%), decreased CD8(%), and elevated CD4/CD8 ratio. No FVIII inhibitor development was observed in any patient. ELISA assay testing for antibodies to rFVIII, baby hamster kidney cell (BHK) protein, and murine IgG were all negative. These results show that rFVIII–FS is a safe and effective for long‐term treatment of patients with haemophilia A.
Molecular pathology of haemophilia A in Turkish patients: identification of 36 independent mutations
Authors: Ti̇mur A. A. , Gürgey A. , Aktugˇlu G. , Kavakli K. , Canatan D. , Olek K. , Çagˇlayan S. H.
Published: March 2003

Haemophilia A is an X‐linked recessive bleeding disorder caused by heterogeneous mutations in the factor VIII gene. In an attempt to reveal the molecular pathology of Turkish haemophilia A patients, the coding sequence of the gene, excluding a large portion of exon 14, was amplified from genomic DNA and subjected to denaturing gradient gel electrophoresis prior to DNA sequencing. Fifty‐nine haemophilia A patients were included in the study with severe, moderate and mild phenotypes observed in 24, 15 and 16 patients, respectively. Factor VIII activity and clinical phenotypes were not available for four patients. A total of 36 independent mutations were found, with a mutation detection efficacy of 61%. The mutations that were reported for the first time include 20 point mutations, one 8‐bp insertion (TCAAGATA) in exon 4 and one large deletion greater than 2.8 kb involving exon 14. The novel point mutations were composed of three nonsense (Ser681Ter, Cys2021Ter and Gln2113Ter), one splicing error (IVS‐1G→A), 15 missense mutations (Lys48Asn; Leu‐98Phe; Thr118Ala; Cys248Tyr; Glu456Lys; Asp560Ala; Tyr664Cys; Phe679Leu; Gly691Trp; Asp1769His; Val1857Leu; Gly2026Gln; Arg2163Pro; Asp2288Ala; and Arg2304Leu) and a T deletion in exon 25 that caused a frameshift followed by a stop codon. All missense mutations except Val1857Leu, which maintained a conserved nonpolar R group, occurred at amino acids conserved among four species and were most probably pathogenic. In addition, two sequence changes (IVS3–9C→T) and (Leu2230Leu) were also detected in patients carrying Val1857Leu and Phe679Leu missense mutations, respectively. Identification of mutation origins in eight sporadic cases revealed an equal sex ratio of mutations.
Clinical outcomes and resource utilization associated with haemophilia care in Europe
Authors: SCHRAMM W. , ROYAL S. , KRONER B. , BERNTORP E. , GIANGRANDE P. , LUDLAM C. , GRINGERI A. , BERGER K. , SZUCS T. ,   FOR THE EUROPEAN HEMOPHILIA ECONOMIC STUDY GROUP
Published: March 2003

We conducted a multicentre, cross‐ sectional study of 1042 haemophilia subjects across Europe to compare various health outcomes associated with on‐demand vs. prophylactic factor‐substitution therapy. Demographic, medical history, and healthcare resource utilization data were analysed along with the number of bleeding events over the past 6 months. Treatment‐cost data were also examined to provide preliminary information for future economic studies. A logistic regression analysis, controlling for other statistically significant covariates, showed that patients treated on demand were 3.4 times more likely to have had a joint bleed over the previous 6 months than those treated with prophylaxis. Multiple regression analyses further confirmed these findings, because on‐demand subjects had, on average, 5.15 more joint bleeds over the reporting period than patients treated with prophylaxis. Notably, these findings were even more dramatic for younger haemophilia patients when our study sample was stratified by age. Due to the high cost of factor replacement, healthcare costs were significantly higher for subjects treated prophylactically. While hospital costs for prophylaxis subjects were, on average, lower, statistically significant cost savings for prophylactic subjects were not noted. These results suggest that clinicians and health policy decision‐makers should consider the advantages of prophylactic therapy for haemophilia patients in formulating treatment protocols and allocating health resources.
Use of recombinant factor IX in subjects with haemophilia B undergoing surgery
Authors: RAGNI M. V. , PASI K. J. , WHITE G. C. , GIANGRANDE P. L. , COURTER S. G. , TUBRIDY K. L. ,   THE RECOMBINANT FIX SURGICAL STUDY GROUP
Published: March 2003

Recombinant human FIX (rFIX) was evaluated in 28 subjects, including 26 with mild, moderate, or severe haemophilia B and two haemophilia B carriers undergoing 36 surgical procedures. Preoperative rFIX dose was highly correlated with postinfusion FIX activity, r=0.61, P=0.0158. Peri‐ and post‐operative estimated blood loss was similar to that expected in non‐haemophilic individuals, and haemostasis was rated as excellent or good in 34 of 35 (97.1%) of the operative procedures. Transfusions were required in five of 36 (13.9%) procedures, including one liver transplantation, and three knee and one hip arthroplasties. Adverse events occurred in 15 of 28 (53.6%) subjects, but there were no perioperative haemorrhages, thromboembolic events, coagulation activation, viral transmission, or inhibitor formation. A transient low‐responding FIX inhibitor developed in one subject preoperatively, but required no change in treatment and resolved 15 months later. Thus, rFIX was found to be safe and effective in achieving haemostasis in subjects with FIX deficiency undergoing surgery.
The treatment of intra‐articular synovitis by the use of chemical and radioactive substances
Authors: HEIM M.
Published: March 2003

As the Chairperson of the session relating the intra‐articular use of chemical and radioactive substances it would seem appropriate to give credit to those who contributed to the recent supplement of our Journal Haemophilia. I have extracted key sentences and concepts from the contributed articles.

All the papers can be found in Haemophilia, Volume 7, Supplement 2, July 2001. The title, authors and page numbers are provided [1].
Total knee replacement in haemophilia
Authors: GODDARD N. J. , RODRIGUEZ‐MERCHAN E. C. , WIEDEL J. D.
Published: March 2003

We believe that total knee replacement (TKR) is a safe and effective procedure for the management of haemophiliac joint arthropathy; however, the increased risk of infection and non‐infective complications remain a cause for concern. TKR in haemophilic patients carries with it an increased risk of post‐operative infection in comparison to non‐haemophiliac patients. Those patients at particular risk are the HIV‐positive haemophiliac patients whose CD4 count is less than 200 cells mm–3. The latest techniques have gone a long way to reducing the complication rate and to achieving results that match those of a similar non‐haemophiliac population.
Prophylaxis in developed and in emerging countries
Authors: TUSELL J. , PÉREZ‐BIANCO R.
Published: March 2003

The significant progress made in recent years in the safety and efficacy of both plasma‐derived and recombinant factor concentrates has allowed treatment programmes to be developed that go beyond the simply curative or the treatment of the consequences of the disease (episodic or on‐demand treatment), enabling the criteria of preventative medicine to be applied to congenital bleeding disorders. The aim of these programmes is to achieve constant, minimum levels of factor in patients above 1 or 2%, thereby converting severe haemophilia into moderate haemophilia.
A randomized study of alpha‐interferon plus ribavirin for 6 months or 12 months for the treatment of chronic hepatitis C in patients with bleeding disorders
Authors: SCHULMAN S. , KINNMAN N. , LINDMARKER P. , VON SYDOW M.
Published: March 2003

Little is known about the optimal treatment in patients with chronic hepatitis C virus (HCV) who were infected by pooled plasma products. The aim of our study was to compare the efficacy of 6 and 12 months of combination therapy with interferon α‐2b and ribavirin in patients with bleeding disorders and chronic HCV. In a randomized open study, 61 patients with haemophilia or von Willebrand disease received treatment with a combination of interferon α‐2b and ribavirin at standard dosage for 6 or 12 months. Follow‐up was done with analysis of HCV RNA after an additional 6 months. The prevalence of HCV genotype 1 was 67%. Overall, sustained viral response was achieved in 41%; 13 of 30 patients (43%) treated for 6 months vs. 12 of 31 patients (39%) treated for 12 months. The rate of sustained response was 22% in those with HCV genotype 1 and 80% in other genotypes (100% in genotype 2), with no difference between the treatment durations. The number of early discontinuations due to side‐effects was 3 and 9, respectively. The study was stopped prematurely due to introduction of a more effective regimen, and the numbers are not sufficient to state equality. We conclude that the efficacy and safety of combination therapy against chronic hepatitis C in patients infected by pooled plasma products is similar to that observed in other populations. Six months of therapy seems sufficient in the case of HCV genotype 2. For other genotypes, the decision regarding duration of therapy has to be based on the tolerance of the individual patient together with experiences from other studies.
Anti‐inhibitor coagulant complex for the rescue therapy of acquired inhibitors to factor VIII: case report and review of the literature
Authors: Kleinman M. B.
Published: March 2003

Summary.  A 62‐year‐old African–American man with a history of hypertension, asthma, and prostate cancer, but no prior history of haemophilia presented with gross haematuria following a motor vehicle accident. Coagulation studies revealed a prolonged partial thromboplastin time. Subsequent mixing study and factor analysis confirmed factor VIII (FVIII) deficiency. The patient subsequently developed a knee haemarthrosis associated with persistent haematuria and a profoundly elevated FVIII inhibitor titre. Fresh frozen plasma was initiated upon presentation. Once FVIII inhibitor was discovered, immunosuppressive agents were started. Concurrent treatment with acute bypass agents including porcine FVIII, and recombinant human factor VIIa (rFVIIa;NovoSeven®), was also given. Ultimately, anti‐inhibitor coagulant complex (Autoplex® T) was administered, stabilizing the haematuria and haemarthrosis. There was no additional bleeding 6 months after the last dose of anti‐inhibitor coagulant complex. This case is consistent with others in which anti‐inhibitor coagulant complex therapy was used successfully to manage patients with serious acute bleeding problems who are found to have acquired inhibitors to factor VIII.
Three novel point mutations causing haemophilia A
Authors: Sukarova‐Stefanovska E. , Zisovski N. , Muratovska O. , Kostova S. , Efremov G. D.
Published: March 2003

Summary.  Haemophilia A is an X‐linked bleeding disorder caused by mutations in the factor VIII gene. In our efforts to elucidate molecular defects in the haemophilia A patients from the Republic of Macedonia, we employed nonradioactive single‐strand conformation polymorphism analysis followed by direct sequencing, for identifying point mutations in the factor VIII gene. In the present study we report the detection of three novel missense mutations: Met‐19→Arg; Ala78→Pro and Cys2174→Gly, all causing haemophilia A.
A blinded in vitro study with Refacto® mock plasma samples: similar FVIII results between the chromogenic assay and a one‐stage assay when using a higher cephalin dilution
Authors: Caron C. , Dautzenberg M‐D. , Delahousse B. , Droulle C. , Pouzol P. , Dubanchet A. , Rothschild C.
Published: March 2003

Summary.  Assay of factor VIII (FVIII) in patient samples is routinely carried out using the one‐stage assay rather than the chromogenic substrate assay. The introduction of new FVIII preparations for the treatment of haemophilia A, including immunopurified FVIII and particularly, recombinant FVIII (rFVIII) concentrates, has led to discrepancies between the results obtained with the two assays. In patients treated with rFVIII concentrates, FVIII levels measured with the one‐stage assay can be 20–50% lower than those measured with the chromogenic assay. In this study, the one‐stage assay was performed with cephalin dilutions higher than those recommended by the manufacturer. B‐domain‐deleted recombinant FVIII, Refacto®, was diluted to eight different concentrations, ranging from 1–100 IU dL−1, in FVIII‐deficient plasma and the FVIII activity of the eight solutions was determined by the chromogenic method in a central laboratory. Aliquots were then assayed by the one‐stage method in the four participating laboratories, using different dilutions of CK‐Prest®. When CK‐Prest® was reconstituted according to the manufacturer's recommendations (dilution 1 : 1), the difference between the one‐stage and chromogenic methods was close to 30%. CK‐Prest® cephalin dilutions of 1 : 5 and 1 : 8 gave very similar results with the two methods, without increasing the interlaboratory coefficient of variation. These findings confirm the influence of phospholipids on the one‐stage assay, particularly the importance of using a phospholipid concentration close to the physiological value in platelets. Thismodified one‐stage method may therefore offer an alternative to the use of a concentrate‐specific standard.
Long‐term follow‐up after osteotomy for haemophilic arthropathy of the knee
Authors: Wallny T. , Saker A. , Hofmann P. , Brackmann H. H. , Nicolay C. , Kraft C. N.
Published: March 2003

Summary.  In this study the long‐term value of corrective osteotomy around the knee was evaluated by means of clinical and radiographic parameters. Between 1974 and 1984 we performed 52 corrective osteotomies in the vicinity of the knee on patients affected by haemophilic arthropathy. Forty‐two patients (45 osteotomies) were adequately followed‐up at an average 11.6 years postoperatively. Using the clinical score of the Advisory Committee of the World Federation of Haemophilia, 38 patients showed a postoperative improvement, five remained clinically unchanged and two showed deterioration. Range of motion of the knee joint did not significantly improve postoperatively. The radiographic Pettersson score showed only a marginal decrease by an average 0.003 points at the time of follow‐up. Only one patient needed subsequent joint replacement of both knees, on the left side 13 years after osteotomy and on the right side 8 years after osteotomy.

Even in cases of marked radiographic joint destruction, corrective osteotomy shows acceptable long‐term clinical results, underlining the feasibility of this management option in the treatment of haemophilic arthropathy of the knee. Although moderate cartilage degenerations in the femoropatellar complex and in the contralateral compartment can be tolerated, this therapy should primarily be contemplated for those patients where damage is unicompartmental and a corresponding axial deviation is found. Particularly the younger patient can benefit from this treatment option in that joint replacement may possibly wholly be avoided or at least postponed to a later stage of life.
Species as units of analysis in ecology and biogeography: time to take the blinders off
Authors: Riddle Brett R. , Hafner David J.
Published: March 2003

Species and their geographical distributions, tabulated either from regional faunal and floral monographs or directly from natural history collections, often are used as the basic units of analysis by ecologists and biogeographers. It has been argued that in order for species to be operationally useful units for evolutionary and ecological studies, they need to be recognizable and identifiable as distinct entities. A growing body of molecular phylogeographic studies demonstrates that currently recognized species often are unreliable in their approximation of fundamental evolutionary and geographical units, leading, for example, to proposed usage of molecular‐based evolutionarily significant units in lieu of species in conservation biology. We argue that ecologists and bio‐ geographers should likewise employ evolutionarily significant units as basic units of analysis when evidence clearly indicates that a formally recognized species either fails to convey important evolutionary and geographical information (i.e. includes multiple geographically distinct evolu‐ tionary lineages) or fails to delineate a natural entity (i.e. does not represent a monophyletic set of populations). We demonstrate the limitations of current species as evolutionary, geographical, and conservation units within the ecologically well‐studied North American desert rodent assemblage. We suggest that biotic surveys should be designed to allow the efficient assembly and dissemination of molecular phylogeographic data from ecologically and biogeographically representative systems.
Global controls of forest line elevation in the northern and southern hemispheres
Authors: Jobbágy Esteban G. , Jackson Robert B.
Published: March 2003

We explored whether the independent evolutionary history of extratropical forests in the southern and northern hemispheres affects the temperature–elevation relationship of mountain forest lines. We compiled 115 forest line descriptions from the literature, covering the major extratropical mountain ranges of the world. We related forest line elevation to thermal regimes using mean annual temperature adjusted to sea level (MAT) and seasonal thermal amplitude (STA, mean of the warmest month minus the mean of the coldest) obtained from a global climate database.
Cetirizine and levocetirizine inhibit eotaxin‐induced eosinophil transendothelial migration through human dermal or lung microvascular endothelial cells
Authors: Thomson L. , Blaylock M. G. , Sexton D. W. , Campbell A. , Walsh G. M.
Published: March 2003

BackgroundSeveral second‐generation antihistamines have documented anti‐inflammatory effects which appear independent of H1‐receptor blockade. We investigated the inhibitory effect of cetirizine and its active enantiomer levocetirizine on eosinophil transendothelial migration (TEM) through monolayers of normal human dermal microvascular endothelial cells (HMVEC‐d) or human lung microvascular endothelial cells (HMVEC‐l).

MethodsHMVEC‐d or HMVEC‐l were grown to confluence on micropore filters in transwells inserted into a 24‐well tissue culture dish. Eosinophils were isolated by density gradient centrifugation and negative immunomagnetic selection. Untreated eosinophils or eosinophils pre‐incubated (30 min at 37 °C) with a concentration range of cetirizine or levocetirizine (10−5to 10−9 m) were added to the upper chamber of the transwell which was incubated for 60 min at 37 °C. Both spontaneous eosinophil TEM and TEM to 100 ng/mL of human eotaxin in the lower chamber were assessed.

ResultsBetween 8 and 10% of the eosinophils added to the upper chamber underwent spontaneous TEM through HMVEC‐d or HMVEC‐l. The addition of eotaxin to the lower chamber enhanced eosinophil TEM through HMVEC‐d or HMVEC‐l monolayers to over 20%, i.e. an enhanced TEM of approximately 100% in each case. Pre‐incubation of eosinophils with cetirizine or levocetirizine dose‐dependently inhibited eosinophil TEM to eotaxin through both HMVEC‐d or HMVEC‐l with total inhibition of eotaxin‐induced TEM observed at 10−8 mfor HMVEC‐d and 10−7 mfor HMVEC‐l. Both drugs gave a reduced but significant inhibition of eosinophil TEM at lower concentrations. No concentration of cetirizine or levocetirizine had any significant effect on expression of CD11b, CD18 or CD49d by either resting or eotaxin‐stimulated eosinophils. Furthermore, no effect on spontaneous eosinophil TEM, or eosinophil viability was seen with any concentration of cetirizine or levocetirizine.

ConclusionLevocetirizine inhibits eotaxin‐induced eosinophil TEM through both dermal and lung microvascular endothelial cells suggesting that, like cetirizine, levocetirizine has potential anti‐inflammatory effects.
Parental farming protects children against atopy: longitudinal evidence involving skin prick tests
Authors: Horak F. , Studnicka M. , Gartner C. , Veiter A. , Tauber E. , Urbanek R. , Frischer T.
Published: March 2003

Background There is growing evidence that the development of allergic sensitization can be influenced by environmental co‐factors. Studies showed that growing up on a farm can protect children against allergic sensitization. However, little is known whether this ‘farming effect’ can only be observed in early lifetime or whether it also plays a role in later childhood.

Objective The aim of our study was to test whether a farming environment is negatively associated with a new occurrence of skin prick test (SPT) positivity in school children. As a secondary outcome we investigated whether children living on a farm lose their allergic sensitization more frequently than other children.

Methods In a longitudinal design, 1150 elementary school children (mean age 7.8 years, SD 0.7) were recruited from nine different areas of Austria in 1994. A questionnaire and an SPT involving seven common aero‐allergens were performed at study entry and at follow‐up 3 years later.

Results A total of 844 children, who underwent two SPTs, were included in the analyses; 15.1% of their families reported working on a farm. Adjusting for potential confounders (parental education, number of siblings, sex, family history of allergy), parental farming was inversely related to the prevalence and new occurrence of SPT positivity [no farming 12.2%, part‐time farming 6%, full‐time farming 2.2% incidence; odds ratio (OR) farming vs. non‐farming 0.34, 95% confidence interval (CI) 0.12–0.98]. Furthermore, children living in a farming environment were more likely to lose their SPT positivity during follow‐up (no farming 14.6%, part‐time farming 50%, full‐time farming 60% loss of sensitization; OR farming vs. non‐farming 8.06; 95% CI 2.05–31.75). No difference in the pattern of sensitization to specific allergens could be observed between farming and non‐farming children.

Conclusion A farming environment has a strong negative effect on the development of allergic sensitization. Furthermore, the study provides evidence that atopic children living on a farm lose their SPT positivity more frequently than children from non‐farming environments.