bluuebunny/crossref_metadata_2025 huggingface dataset:
Progression of HIV in haemophilia
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , RAGNI M. V.
Published: March 2003

Summary. The recent elucidation of the life cycle and dynamics of the human immunodeficiency virus (HIV) and technological advances in development of the HIV RNA PCR assay for sensitive detection of viral load have revolutionized the diagnosis, management, and treatment of HIV infection. Beginning with initial infection, there is unremitting, high‐level viral replication that persists throughout the course of HIV infection. The measure of the amount of virus present in plasma, HIV viral load, is the single most important predictor of HIV progression, the best indicator of immune system decline, and the best guide for initiating and monitoring antiviral treatment. Further, HIV viral load has become the new yardstick against which other markers, including CD4 number, age, chemokine receptor mutations, cytotoxic T‐cell responses, and neutralizing antibody titers are assessed. For individuals with haemophilia, additional ‘markers’ may have significant impact on the outcome of HIV disease. Chronic factor concentrate treatment has led to transfusion‐associated hepatitis, co‐infection with hepatitis C (HCV), and chronic liver disease. The latter may become accelerated with HIV progression and may lead to hepatotoxicity with antiviral drug therapy. Chronic factor concentrate treatment has also been associated with immunosuppression, including both B‐ and T‐cell immune defects. In HIV(+) haemophilic men, this immune deficit has led to lower CD4 counts with HIV progression and poorer CD4 response to antiviral drugs than in gay men. The underlying haemophilic bleeding tendency may result in significant haemorrhage with HIV‐associated immune thrombocytopenia and with protease inhibitor antiretroviral therapy. Although AIDS is the leading cause of death in this group, the reduction in the size of the haemophilia population over the next two centuries is estimated to be small, and survival should improve as better antiviral therapeutics are identified.
Quality control and factor VIII assays
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , PRESTON F. E. , KITCHEN S.
Published: March 2003

Summary. Quality assurance is a vital prerequisite of good laboratory practice. The application and continuous scrutiny of adequate internal quality control measures are essential to ensure that laboratory performance is consistent from day to day. External quality assessment is particularly important to verify the accuracy and reliability of laboratory results Consequently, without appropriate IQC and EQA, laboratory results can have no true validity.
Current practices regarding newborn intracranial haemorrhage and obstetrical care and mode of delivery of pregnant haemophilia carriers: a survey of obstetricians, neonatologists and haematologists in the United States, on behalf of the National Hemophilia Foundation’s Medical and Scientific Advisory Council
Authors: Kulkarni  , Lusher  , Henry  , Kallen
Published: March 2003

We undertook this survey to determine institutional practices of obstetricians, neonatologists and haematologists regarding care of pregnant haemophilia carriers and newborns with haemophilia and intracranial haemorrhage (ICH). Our purpose was also to determine whether institutions had written guidelines to manage such patients. Questionnaires were sent to 1000 obstetricians and through the Haemophilia Treatment Centres (HTC) to 180 paediatric haematologists and 180 neonatologists, each representing an institution.

Twenty‐three per cent of obstetricians, 22% of neonatologists and 16% of paediatric haematologists returned completed surveys. Over 94% of the respondents had no written guidelines for management of pregnant haemophilia carriers or their newborns or for neurologic assessment of newborns. For known haemophilia carriers, 57% of the obstetricians routinely preferred vaginal delivery and 11% preferred caesarean section. Availability of perinatal services influenced prenatal management (P < 0.05). In term newborns with documented ICH, only 23% of neonatologists would evaluate for haemophilia, whereas in pre‐term newborns with ICH, this number dropped even further to 3%. For all newborns with haemophilia, 40% preferred routine administration of clotting factor concentrates (CFC) immediately following birth to offset the trauma of delivery and 89% of paediatric haematologists favoured early prophylaxis with CFC.

Guidelines are needed for management of pregnant haemophilia carriers as well as newborns with haemophilia. Physicians need to be made aware that ICH may be a presenting sign of haemophilia in both term as well as pre‐term newborns, so that appropriate therapy can be instituted early in the event of a bleed.
The molecular biology of von Willebrand disease
Authors: Ginsburg D.
Published: March 2003

von Willebrand disease is the most common inherited bleeding disorder in humans, with the general population prevalence estimated to be as high as 1% in some studies. This condition exhibits extensive heterogeneity with over 20 distinct subtypes distinguished based on subtle clinical and laboratory differences in presentation. Recent research laboratory advances have shed considerable new light on the molecular basis of this disorder. Specific mutations within the von Willebrand factor gene have been identified in many of the qualitative variants of von Willebrand disease, providing important new insight into the structure and function of this central clotting protein. However, the complex genetic factors determining the clinical severity of type 1 von Willebrand disease, the most common variant, still remain largely unknown and are the subject of current investigation.
Clinical efficacy and recovery levels of recombinant FVIIa (NovoSeven) in the treatment of intracranial haemorrhage in severe neonatal FVII deficiency
Authors: Wong  , Huang  , Miller  , Mcginty  , Whisnant
Published: March 2003

The use of replacement FVII is critical to the successful treatment of life‐threatening bleeds in newborns and infants with severe FVII deficiency (<1%). However, the clinical efficacy, optimum dosage and pharmacologic recovery of rFVIIa in such children has not been studied systematically. This report is a case of an infant with severe FVII deficiency (FVII:C at 0%) and massive intracranial haemorrhage in which successful use of rFVIIa (NovoSeven) was carefully monitored. The drug was administered by intravenous bolus through a central line every 4 h at each of three dose levels: 15 μg kg–1, 22 μg kg–1 and 30 μg kg–1. FVII:C was >100% between 30 and 180 min after each infusion with mean trough levels above 25% for all three dose levels. There was no evidence of hyper‐coagulation as indicated by measurements of the platelet count,
D‐dimer, plasma protamine paracoagulant and fibrinogen levels in spite of high FVII:C concentration.

In this infant, rFVIIa was well‐tolerated, maintained effective haemostasis with good clinical outcome, and produced consistent therapeutic mean trough levels above 25% FVII:C even at 15 μg kg–1 every 4 h.
Immune tolerance induction in the treatment of paediatric haemophilia A patients with factor VIII inhibitors
Authors: Unuvar A. , Warrier I. , Lusher J. M.
Published: March 2003

The development of an inhibitor to transfused factor VIII (FVIII) is a serious treatment‐related problem in haemophiliac children. The management of patients with high titre FVIII inhibitors is difficult, and immune tolerance induction (ITI) is the only method available for the eradication of these inhibitors. The results of the ITI regimen used at the Children’s Hospital of Michigan Haemophilia Treatment Center are described and discussed. ITI was attempted in 14 children with severe haemophilia A (13 high responders, one low responder), with daily doses of FVIII alone. FVIII dosage was chosen according to the patient’s historical peak inhibitor titre. ITI included three phases; induction phase, dose reduction phase and maintenance phase. During the first phase, the starting dose was 50 or 100 U kg–1 d–1; during the second phase the FVIII dosage was reduced gradually to 25 U kg–1 every other day according to the inhibitor titre, FVIII recovery and/or half‐life study. In the third (maintenance) phase, the children received either prophylactic therapy or episodic therapy for 12 months. The inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half‐life. Immune tolerance was achieved in 11 of 14 patients (79%) patients within a median time of 6 months; two children are still on therapy, three failed ITI. We observed either failure or prolongation of immune tolerance if the historical peak titre or the maximum titre during ITI was >200 BU. The success rate of our low dose ITI regimen is not different from that reported by other investigators and the inhibitor elimination time is similar to some of the studies reported previously.
Intra‐articular hyaluronic acid in the treatment of haemophilic arthropathy of the knee. Clinical, radiological and sonographical assessment
Authors: Wallny  , Brackmann  , Semper  , Schumpe  , Effenberger  , Heß  , Seuser
Published: March 2003

Hyaluronic acid has been used successfully in the treatment of osteoarthritis since 1989. There is no experience in haemophiliacs in larger study groups. In a prospective study, 20 patients (21 knees) with haemophilic arthropathy of the knee received 20 mg hyaluronic acid by intra‐articular injection for 5 consecutive weeks. Assessment included clinical scores, X‐ray, magnetic resonance imaging (MRI) and biomechanical motion analysis before and 3 months after the first injection. The score of the WFH advisory committee and the Aichroth score for special evaluation of the knee were used. After an average period of 26 months, the World Federation of Hemophilia (WFH) score, the Aichroth score and the visual analogue scale were evaluated again. All patients had pain caused by their arthropathy, nine of them had positive antibodies to human immunodeficiency virus, and 15 had chronic hepatitis C. The mean WFH score was 8.1 points, the Petterson score was 7.3 points and the Aichroth score was 38 points (maximum 55 points). The WFH score decreased to 7.3 points, the Aichroth score improved to 40 points and the subjective assessment measured with a visual analogue scale improved from 5.3 to 3.7 points. No differences from MRI controls were detected. After 3 months, 14 of 20 patients improved subjectively, particularly in longer walking distance, stair‐climbing or initial pain. These positive aspects were limited by arthropathy in adjacent joints. After 26 months 10 patients still are benefiting for up to 31 months follow‐up. The average WFH score was 7.3 points, the Aichroth score 39 points, the visual analogue scale 4.0 points. We recommend hyaluronic acid for haemophilic arthropathy of the knee when regular conservative therapy has failed and operative treatment is not feasible.
Venous thromboembolism after hip fracture surgery in a patient with haemophilia B and factor V Arg506Gln (factor V Leiden)
Authors: Pruthi R. K. , Heit J. A. , Green M. M. , Emiliusen L. M. , Nichols W. L. , Wilke J. L. , Gastineau D. A.
Published: March 2003

We describe a patient with mild haemophilia B who developed symptomatic venous thromboembolism after hip arthroplasty for a traumatic fracture. A deep vein thrombosis developed in the operated leg while he was receiving a high‐purity factor IX concentrate. Subsequently, he was determined to be a heterozygous carrier for the factor V Arg506Gln (Leiden) mutation. This case illustrates the importance of providing thromboprophylaxis for all patients with haemophilia receiving coagulation factor replacement and who undergo surgical procedures known to be associated with a high risk of venous thromboembolism. In patients with haemophilia and a family history of venous thromboembolism, preoperative screening for the presence of the factor V Arg506Gln mutation and other thrombophilias may be useful.
Gynaecological and obstetrical morbidity in women with type I von Willebrand disease: results of a patient survey
Authors: Kouides P. A. , Phatak P. D. , Burkart P. , Braggins C. , Cox C. , Bernstein Z. , Belling L. , Holmberg P. , Maclaughlin W. , Howard F.
Published: March 2003

Type 1 von Willebrand disease (vWD) is generally regarded clinically as ‘mild’ and the obstetrical–gynaecological features have not been fully described. We administered a patient questionnaire and provider survey of the medical and quality of life aspects of childbirth and menstruation to 99 type 1 vWD patients and compared the patients presently menstruating (n=81) to a cohort of 150 menstruating females in the general population. The following measurements had a statistically higher proportion in the vWD group: number of tampons/towels used for a typical menstrual cycle (P=0.002); percentage reporting that clothes are stained by menses (P = 0.001); past or present history of anaemia (P = 0.001); childbirth‐related bleeding (P=0.001); and childbirth‐related bleeding necessitating RBC transfusion (P=0.002). Quality of life assessment of the impact of menses in both of the above cohorts was measured by a Likert scale using seven quality of life parameters. Compared to the control group, the vWD patients had a significantly higher score, with P‐values of < 0.0001 for each parameter. Hormonal interventions for menorrhagia in the vWD patients were ≤ 50% effective. Menorrhagia resulted in red blood cell transfusions in 6% of patients, dilatation and curettage in 17% and hysterectomy in 13%. Despite the common connotation of type 1 vWD as clinically ‘mild’, childbirth and the monthly challenge to haemostasis presented by menstruation result in a substantial degree of morbidity in females with type 1 vWD. These results support the rationale for ongoing international efforts to increase awareness of vWD as a cause for menorrhagia and to improve the quality of life in females with known vWD.
The future of plasma‐derived clotting factor concentrates
Authors: Hoots W.K.
Published: March 2003

In developed countries, preferred treatments for both haemophilia A and B have moved toward recombinant clotting factor concentrates, while plasma‐derived replacement therapies are still required by many patients. Great improvements have been made in producing relatively pathogen‐free clotting factor replacements from pooled plasma. The fluidity and complexity of the worldwide plasma product market are discussed in the context of the ‘yin and yang’ of plasma therapeutics, showing how multiple issues can influence the safety and availability of clotting factor concentrates. Use of plasma‐derived products will likely continue for the next decade for patients with inhibitors, patients with von Willebrand disease, those requiring bypassing agents, in immune tolerance induction, and for treatment of rare inherited deficiencies of procoagulant or anticoagulant proteins. Furthermore, in developing countries many of the most advanced therapies are not available for the majority of haemophilia patients, and thus plasma‐derived replacement concentrates will continue to be used even for noninhibitor patients.
Combined prednisolone and intravenous immunoglobulin treatment for acquired factor VIII inhibitors: a 2‐year review
Authors: Dykes A. C. , Walker I. D. , Lowe G. D. O. , Tait R. C.
Published: March 2003

Acquired inhibitors to factor VIII (FVIII) are rare, but life‐threatening in up to 22% of cases. The optimal therapy for suppression of these inhibitors remains unclear. Prednisolone is the mainstay of therapy, producing responses in approximately 30% of cases. Intravenous immunoglobulin (IVIg) has a similar response rate, but a more rapid effect. We report the results of prednisolone 1 mg kg−1 combined with IVIg 2 g kg−1 in divided doses as first‐line therapy in seven consecutive patients with acquired FVIII inhibitors. All patients were bleeding at the time of diagnosis with prolonged activated partial thromboplastin time. There were four complete responses, one partial response, one nonresponse and one with an inadequate follow‐up for assessment of response, giving an overall response rate of 71%. In all complete responders the inhibitor declined rapidly and was undetectable by day 21 from start of treatment. Therapy was well tolerated and responses have been maintained off treatment for 2–8 months. This is a safe, well‐tolerated rapidly acting regimen with good response rates.
Assessing the relationship between productivity levels and severity of haemophilia
Authors: Miners A. H. , Sabin C. A. , Tolley K. H. , Parnaby A. , Lee C. A.
Published: March 2003

In this study, we assessed whether severity of haemophilia was associated with levels of productivity. Productivity levels were assessed by sending a ‘time‐use’ questionnaire to 228 individuals with mild, moderate and severe haemophilia. The results showed that, after adjusting for differences in age and HIV serostatus, there were no differences between individuals with severe and mild/moderate haemophilia in terms of completed levels of education, employment status, absenteeism from work over the previous 2 weeks, the number of hours each week spent performing unpaid tasks and how efficiently individuals performed these tasks. The data did suggest, however, that a significantly larger proportion of individuals with severe haemophilia (32%) required help from family or friends to perform routine household tasks each week than individuals with mild/moderate haemophilia (13%). In conclusion, it is possible that individuals with severe haemophilia have similar levels of productivity compared to individuals with mild/moderate haemophilia or that treatment with secondary prophylaxis has helped to reduce differences between the two patient groups.
Porcine factor VIII in the treatment of high‐titre inhibitor patients
Authors: Garvey M.B.
Published: March 2003

Development of an inhibitor against factor VIII (FVIII) is an important complication of haemophilia. It occurs in approximately 25–30% of patients with haemophilia A [1]. FVIII inhibitors may also occur as autoantibodies. The latter occur in nonhaemophiliacs and, although rare (occurring in approximately one per million of the population), are frequently associated with life‐threatening bleeding. Inhibitors are considered low level if they are < 5 Bethesda Units (BU) or high level if they are > 10 BU. The former usually remain low and rarely give anamnestic response, the latter do so frequently. Despite various approaches to their management, the presence of inhibitors remains a major cause of morbidity and mortality. The effectiveness of porcine FVIII (pFVIII) in treating patients with both auto‐ and alloantibodies to FVIII has been well demonstrated when adequate circulating levels of FVIII are obtained [2–10]. However, pFVIII therapy may give rise to antibodies to the pFVIII and the utility of this treatment in the presence of high levels of porcine antibody is less well recognized and understood. Nonetheless, pFVIII under these circumstances may be useful in a select group of patients where management is difficult.
Continuous infusion of porcine factor VIII: stability, microbiological safety and clinical experience
Authors: DiMichele D.M. , Gorman P.O. , Kasper C.K. , Mannucci P.M. , Santagostino E. , Hay C.R.M.
Published: March 2003

Porcine factor VIII (pFVIII) is an effective haemostatic treatment for bleeding in selected patients with FVIII inhibitors. Its use is sometimes associated with a transient fall in platelet count and transfusion reactions, the risk of which may be related to the rate of administration. Theoretical considerations suggest that the administration of pFVIII by continuous infusion should be effective, and could have pharmacokinetic advantages that lead to an improvement in the side‐effect profile. The results of a retrospective survey of continuous infusion of pFVIII with respect to clinical safety and efficacy are reported. Porcine FVIII stability and microbiological studies are included. It is concluded that pFVIII given by continuous infusion is safe and effective. The risk of transfusion reactions and fall in platelet count appears to be reduced, compared with bolus administration. Stability studies showed that pFVIII activity declined at room temperature, most rapidly in the dilute solution (5–10 U mL−1). More concentrated mixtures showed acceptable stability for up to 24 h using a variety of infusion devices. Various concentrations of pFVIII did not support the growth of Escherichia coli or Staphylococcus aureus. These observations suggest that the porcine factor is suitable for continuous infusion (CI).
Haemophilia care in the developing world: benchmarking for excellence
Authors: ISARANGKURA P.
Published: March 2003

Seventy‐five percent of patients with haemophilia receive no or inadequate treatment, and often do not survive to adulthood. With efficient organization, the disorder is treatable and becomes part of normal life. In developing countries there is a large discrepancy in haemophilia care. Some have zero treatment levels, while others already have comprehensive care centres. This paper attempts to assess and standardize the levels of haemophilia care for developing countries, setting up benchmarks or guidelines for future development. Four major areas are emphasized: clinical care, laboratory, blood products and patient organization. For each country or community, development work begins after the assessment of competency level in each area. The next step is then to plan, organize, improve and move up to the next level. To become successful, a sound and realistic strategy should be employed, starting from the identification of key leaders and the recruitment of an expert team. To obtain recognition and support from health authorities, the haemophilia care programme should not limit itself to haemophilia care but should also include medical care for all bleeding disorders, including the improvement of blood banks, blood products, coagulation laboratories and other medical facilities. This would directly improve the overall medical care standard of the whole hospital. It is also important to emphasize the need for selfreliance, employing simple yet effective methodology, equipment and mechanical facilities. The effective coordination of World Federation of Hemophilia assistance and the host country's committed action will ensure success in the emerging trend of better haemophilia care in developing countries.
Menorrhagia from a haematologist's point of view. Part I: initial evaluation
Authors: Kouides P. A.
Published: March 2003

Summary.  The evaluation of menorrhagia should no longer be solely the task of the gynaecologist. In women with ovulatory bleeding (regular cycles), the prevalence of von Willebrand disease (vWD) in about 15% of these, as well as disorders of platelet function and fibrinolysis causing menorrhagia, warrants an active role by the haematologist. Initial intake should include documentation of menorrhagia by the pictorial chart assessment of menstrual flow. Baseline characteristics of menstrual flow should also be documented, including the frequency of changing the sanitary pad on the heaviest day, use of more than one sanitary pad at a time, number of days lost␣from school/work and the impact of menses on␣various quality‐of‐life parameters. Menorrhagia since menarche, a past history of surgical‐ and/or dental‐related bleeding and a past history of postpartum haemorrhage are items of the bleeding symptom audit that appear in part to predict vWD in women with menorrhagia. Epistaxis and easy bruising do not appear to be clearly discriminatory symptoms. Initial testing should include the complete blood cell count, prothrombin time, activated partial thromboplastin time, iron profile, serum creatinine, thyroid stimulating hormone level, factor VIII level, vWF antigen, ristocetin cofactor and platelet aggregation studies. Additional haemostatic studies may also include a factor XI level and euglobulin clot lysis time. This extensive medical evaluation should assure both the patient and the gynaecologist that the possibility of an underlying haemostatic disorder has been thoroughly investigated, to avoid the patient undergoing further costly procedures and surgical interventions if an underlying haemostatic disorder remains unrecognized.
MonoFIX‐VF, a new mono‐component factor IX concentrate: a single‐centre continuous‐infusion study
Authors: EVANS G. , COLLETT M. , CAME N. , LLOYD J. , POWELL L. , STREET A.
Published: March 2003

Summary.  MonoFIX‐VF, a monocomponent factor IX concentrate, has replaced the use of Prothrombinex‐HT as the treatment of choice for patients with factor IX deficiency in Australia. The haemostatic effect of MonoFIX‐VF, administered by continuous infusion, was assessed in four subjects being treated for 10 bleeding episodes including five surgical procedures. MonoFIX‐VF was found to be a safe and effective treatment for patients with haemophilia B.
Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic phenotype in severe congenital haemophilia
Authors: Grünewald M. , Siegemund A. , Grünewald A. , Konegen A. , Koksch M. , Griesshammer M.
Published: March 2003

Summary. To elucidate potential causes for differing bleeding phenotypes of haemophilic patients of identical degree of coagulation factor deficiency, we investigated 21 male patients with severe haemophilia. Median annual coagulation factor demand and the extent of haemophilic arthropathy were used to discriminate between intensely and less intensely haemorrhagic phenotypes. Haemophiliacs with a median annual coagulation factor demand of 800 IU per kg bodyweight or more and with three or more joints affected by haemophilic arthropathy represented the intensely haemorrhagic phenotype group; all other patients comprised the less intense group. The discriminator values represent the respective medians of the overall group. The results of activated partial thromboplastin time, endogenous thrombin potential, pro‐ and anticoagulant factor analysis did not differ between the two groups. Median tissue‐type plasminogen activator concentration (TPA) was elevated significantly in haemophiliacs with an intensely haemorrhagic phenotype, as was the activity of the thrombin‐activatable fibrinolysis inhibitor. Median activity of the plasminogen activator inhibitor 1 (PAI 1) and the concentration of TPA–PAI 1 complexes were increased to approximately double those in nonsevere haemophiliacs. Coexistent congenital thrombophilia was found significantly more often in the less intensely haemorrhagic group. Thus, increased stimulation of the fibrinolytic system was associated with a more intensely haemorrhagic phenotype in our patients. We hypothesize that ineffective haemophilic haemostasis in response to trauma evokes a protracted stimulation of the entire haemostatic system, including costimulation of fibrinolysis. The absence of coexistent congenital thrombophilia predisposes to excess stimulation of fibrinolysis, which cannot be downregulated effectively due to the dysfunctional intrinsic pathway. The association of a more intensely haemorrhagic phenotype with a paradoxical hyperstimulation of the fibrinolytic system resembles a vicious circle, where bleeding seems to cause predisposition to more bleeding.
Bone marrow mesenchymal cells for haemophilia A gene therapy using retroviral vectors with modified long‐terminal repeats
Authors: Van Damme A. , Chuah M. K. L. , Dell'accio F. , De Bari C. , Luyten F. , Collen D. , VandenDriessche T.
Published: March 2003

Summary. Bone marrow (BM) cells are attractive target cells for ex vivo gene therapy of genetic diseases, including haemophilia A. However, BM‐derived haematopoietic stem/progenitor cells (HSCs) transduced with factor VIII (FVIII) retroviral vectors, failed to express FVIII in vivo. To overcome the limitations of HSCs for haemophilia gene therapy, BM‐derived mesenchymal cells were explored as alternative target cells. The BM mesenchymal cell population contains self‐renewing mesenchymal stem/progenitor cells that give rise to different mesenchymal lineages and have been used safely in phase I gene‐marking trials. Human BM mesenchymal cells were transduced in vitro with an improved retroviral vector encoding a human B‐domain deleted FVIII (hFVIIIΔB) cDNA (MND‐MFG‐hFVIIIΔB). This vector contains multiple modifications in the cis‐acting elements within the MoMLV long‐terminal repeats (LTR) that prevent the binding of repressive transcription factors. These modifications were previously shown to increase and prolong gene expression in embryonic stem (ES) cells and HSCs. Transduction of BM mesenchymal cells with the MND‐MFG‐hFVIIIΔB retroviral vector resulted in high levels of functional human FVIII in vitro, ranging between 300 ± 50 SD and 700 ± 100 SD mU per 106 cells per 24 h. Following xenografting of the transduced human BM cells into immunodeficient NOD‐SCID mice, therapeutic hFVIII levels of 12 ± 10 ng mL−1 were detected in the plasma. Polymerase chain reaction analysis demonstrated long‐term engraftment (>3 months) of the human BM mesenchymal cells. The long‐term persistence of BM mesenchymal cells in the absence of myelo‐ablative conditioning and the therapeutic FVIII levels in vivo underscore the potential usefulness of BM‐derived mesenchymal cells for haemophilia gene therapy, as opposed to BM‐derived HSCs. Despite the modifications of the MoMLV LTR, FVIII expression declined, which coincided with a decrease in FVIII mRNA transcription levels, indicating that the salutary effect of the LTR modification on transgene expression is not universally applicable to all cell types.
Analysis of haemophilia B database and strategies for identification of common point mutations in the factor IX gene
Authors: Mukherjee S. , Mukhopadhyay A. , Chaudhuri K. , Ray K.
Published: March 2003

Summary.  Haemophilia B is an X‐linked recessively inherited bleeding disorder caused by heterogeneous mutations spanning the entire factor IX gene. As spontaneous germ‐line mutations are known to occur mostly at CpG dinucleotides in the FIX gene, control of the disease would require continuous carrier detection and mutation screening. Identification of point mutations, the most common type of mutation in FIX gene, is more challenging compared with deletion and insertion mutations. We examined the haemophilia B database to identify specific nucleotides in the FIX gene that are mutated in relatively large number of patients and the variability (if any) in the mutational hotspots at CpG dinucleotides. It was found that while mutations responsible to account for all 2348 haemophilia B patients covered 20% of the FIX cDNA, only 1% of the cDNA involving mostly CpG dinucleotides accounted for mutation in 42.41% of the patient pool. Thus, only 27 nucleotides need to be investigated to identify the common point mutations, among which 15 are predicted to undergo change in restriction sites on mutation. It is interesting to note that seven nucleotides occurring in CpG dinucleotides do not have any reported mutation despite each of those being predicted to harbour mutation as a result of transition and having mutations recorded in the database for the neighbouring nucleotides. Strikingly large number of mutation in codon 296 causing T to M change in catalytic domain originally proposed to be the result of the founder effect also contains largest number of haplotype suggesting recurrence of de novo mutation.
Suicide and self‐harm in in‐patient psychiatric units: a study of nursing issues in 31 cases
Authors: Gournay Kevin , Bowers Len
Published: March 2003

Suicide and self‐harm in in‐patient psychiatric units: a study of nursing issues in 31 cases

A significant number of incidents of suicide and self‐harm occur whilst patients are in receipt of care as in‐patients. This audit comprises 31 cases which were referred to the first author for expert opinion, each case being the subject of legal action brought by patients and/or their families. The cases were referred from 31 different NHS trusts across England. All concerned suicide/serious self‐harm in people in receipt of in‐patient care. The aims of this audit were to carry out a detailed assessment of the 31 individual cases, so as to provide a nursing dimension to already established enquiries in this area and also to examine whether specific issues might be the subject of more systematic research. Further, this paper aims to provide some insights in the area of litigation, where nurses are becoming increasingly involved. The same broad approach to information‐gathering and analysis was used, comprising a systematic review of case records, trust policies, expert reports and, where appropriate, inquest transcriptions. The sample comprised 12 suicides and 19 cases of serious self‐harm. Factors associated with these events include: being male, having a dual diagnosis of mental illness and drug/alcohol abuse, and age between 21 and 30 years. Of the 12 deaths, five occurred in hospital, four by hanging and one by drowning. The audit highlighted environmental factors associated with these events which, arguably, could be simply addressed. There was a considerable variation in the content and quality of observation policy and practice. The results of this audit point to the need for further research but, above all, provide evidence requiring urgent action by the Department of Health regarding the setting of national standards.
M3 muscarinic receptors but not M2 mediate contraction of the porcine detrusor muscle in vitro
Authors: Sellers D. J. , Yamanishi T. , Chapple C. R. , Couldwell C. , Yasuda K. , Chess‐Williams R.
Published: March 2003

1 The objective of the study was to determine the role of muscarinic receptor subtypes in mediating contraction of the porcine detrusor smooth muscle in vitro.  2 Strips of pig detrusor muscle were set up in physiological salt solution and the tensions developed by the tissues were recorded. Responses to carbachol were obtained in the absence and presence of a range of muscarinic antagonists (4‐DAMP, methoctramine, darifenacin, oxybutynin, tolterodine and pirenzepine). Antagonist affinity values (pKB values) were calculated and compared with those quoted in the literature for these antagonists at each of the muscarinic receptor subtypes.  3 The M3‐selective antagonists, 4‐DAMP and darifenacin had high affinities (pKB values of 9.4 and 8.6, respectively). Oxybutynin, tolterodine and pirenzepine had affinities of 8.2, 8.1 and 6.8, respectively, whilst the M2‐selective agent methoctramine had a relatively low affinity (pKB=6.1). The rank order of affinities was, therefore, 4‐DAMP>darifenacin>oxybutynin>tolterodine>pirenzepine>methoctramine for the pig detrusor. Correlation of the antagonist affinities obtained on the bladder with those published for these antagonists at the five muscarinic receptor subtypes identified the M3(m3)‐receptor as the muscarinic subtype mediating detrusor contractile responses in vitro.  4 These data suggest that a small population of M3‐muscarinic receptors must mediate direct contractile responses of the pig detrusor muscle to muscarinic receptor stimulation in vitro.
Mangrove transgression into saltmarsh environments in south‐east Australia
Authors: Saintilan Neil , Williams Robert J.
Published: March 2003

The landward transgression of man‐ groves into saltmarsh environments in the estuaries of south‐east Australia over the last five decades is established as a widespread trend through a review of a number of independent studies. This process is occurring in a range of geomorphic settings, and in some cases reversing the direction of longer‐term vegetation change. Several hypotheses are advanced to explain this occurrence, including increases in rainfall, revegetation of areas cleared for agriculture, altered tidal regimes or estuary water levels, and increases in nutrient levels and sedimentation.
A history of fear: imagining deforestation in the West African dryland forests
Authors: Ribot Jesse C.
Published: March 2003

Urban demand for woodfuels in Sudanian and Sahelian West Africa has long been assumed to contribute to permanent deforestation in dryland forests and wooded savannas. Deforestation has also long been assumed to be progressing such that these woodlands will no longer be able to provide the region's cities with fuel. Available studies of regeneration do not support the first assumption. Further, woodfuel shortages projected in the 1980s to arrive in the 1990s or early 2000s are nowhere near, while more recent projections predict supply shortages another 25 years hence. While there is deforestation from many causes, the data do not support crisis scenarios concerning woodfuels. Nonetheless, crisis scenarios and policies persist. While there may yet be deforestation due to urban woodfuel extraction, and shortages may be lurking on the horizon, the article explores some possible alternative origins of these woodfuel related deforestation and shortage fears.
New data on the history of the plateau forest of Okomu, southern Nigeria: an insight into how human disturbance has shaped the African rain forest
Authors: White LeE. J. T. , Oates JohN. F.
Published: March 2003

The classic 1955 and 1956 papers by Eustace Jones describe vegetation pattern, process and history in Okomu Forest, south‐western Nigeria. Jones and colleagues were puzzled to find an extensive layer of charcoal and pottery below mature mahogany forests. Based on an extensive review of historical documents and the estimated ages of dying emergent tree species, Jones suggested that the forest in Okomu had regenerated after a human population decline 200–300 years previously. We made radiocarbon measurements on samples from the layer of charcoal and pottery described by Jones. In addition, we obtained δ13C measures from a soil profile cutting through the charcoal layer. The charcoal dates to about 700–750 years BP whilst the δ13C profile showed no evidence of input of organic matter from C4 grasses. These results are discussed in the light of other recent archaeological evidence of the impact of humans on the rain forests of Africa during the last 2000–3000 years. It seems that extensive archaeological remains are hidden beneath much of the African rain forest, suggesting that human disturbance has been one of the dominant factors affecting forest structure and composition in recent millennia.
A call for a new paradigm of island biogeography
Authors: Lomolino MarK. V.
Published: March 2003

MacArthur and Wilson’s equilibrium theory of island biogeography quickly became the paradigm of the field in the 1960s and has strongly influenced this and other disciplines of ecology and conservation biology for the past three decades. Recently, however, a growing number of ecologists have begun to question whether the theory remains a useful paradigm for modern ecology. We now have a much better appreciation for the complexity of nature and we study patterns that span a very broad range in spatial, temporal and ecological scales. At such scales, assumptions that communities are in equilibrium, that species, islands and intervening landscapes or seascapes are equivalent or homogeneous with respect to factors influencing immigration and extinction, and that in situ speciation can be overlooked become very tenuous. With this in mind, this and other papers of this special feature discuss the principal, conceptual shortcomings of the equilibrium theory and offer some modifications or alternatives to the theory that we hope will eventually lead to a more comprehensive understanding of the forces structuring insular communities.
A species‐based theory of insular zoogeography
Authors: Lomolino Mark V.
Published: March 2003

I present an alternative to the equilibrium theory of island biogeography, one which is based on the premise that many of the more general patterns in insular community structure result from, not despite, nonrandom variation among species.

For the sake of simplicity, the model is limited to patterns and processes operating over scales of ecological space and time: evolution is not included in the current version of the model.

The model assumes, as did MacArthur and Wilson’s model, that insular community structure is dynamic in ecological time, but the model does not assume a balance, or equilibrium, of immigration and extinction.

The model presented here is hierarchical, phenomenological (it requires little parameterization beyond that which is directly derived from distributional data), graphical, and it includes potential feedback processes (including interspecific interactions).

The model offers an alternative explanation for a variety of patterns ranging from distributions of individual species, species–area and species–isolation relationships, to patterns of assembly of insular communities. The model also generates some new predictions and identifies some potentially important areas for future studies.
The role of local and regional processes in shaping dung beetle communities in tropical forest plantations in Borneo
Authors: Davis Andrew J. , Huijbregts Hans , Krikken Jan
Published: March 2003

We examine whether rain forest dung beetle species found in plantations in Sabah, northern Borneo, tend to be endemic or geographically widespread. In addition, linear regressions of abundance vs. distance from a major river in primary rain forest are calculated to see if species found in plantation forest show affinity to one specific biotope (riverine vs. interior forest) in their natural habitat. Results show that 14 of the 40 species recorded from plantations are endemic to Borneo. Only edge‐specialist endemic species are found in plantation forest, with no interior‐forest specialists recorded. Data suggest that endemic species that are adapted to more exposed conditions in primary rain forest, such as riverine species, can in some instances tolerate man‐made habitats. Twenty‐nine species (±SE 4.0) per transect are recorded from plantation transects, whereas 44.2 (±1.7 SE) are recorded in primary rain forest. As species richness is much lower in plantations than natural forest, implying loss of biodiversity, we conclude that measures of biogeographic distinctiveness, whereby endemic species confer higher values, may be misleading unless they take into account edge‐affinity. Local‐ as well as regional‐distributional data may therefore be needed to interpret correctly patterns of species assemblages in derived forest ecosystems.
Biogeographic history of geminate cirrhitoids (Perciformes: Cirrhitoidea) with east–west allopatric distributions across southern Australia, based on molecular data
Authors: Burridge Christopher P.
Published: March 2003

The biogeographic history of three cirrhitoid species pairs with east–west allopatric distributions across southern Australia was examined by determining levels of mitochondrial DNA sequence divergence and applying molecular clock calibrations. Similar levels of genetic divergence were observed for Aplodactylus Valenciennes and Goniistius Gill species pairs, but these were more than twice that observed for a Nemadactylus Richardson pair. Molecular clock calibrations suggested divergences occurred during the late Miocene and mid Pliocene, respectively. Given evidence of high dispersal capabilities, the habitat and climatic barriers of the Australian south coast appear too small to have facilitated speciation of the cirrhitoids examined. A mechanism is proposed by which ancestral cirrhitoids were vicariantly isolated into east and west coast populations during periods of climate change. Although Aplodactylus and Goniistius divergences occurred during the same period, separate vicariant events across the Australian north and south coasts are invoked.
Increases in collagen type I synthesis in asthma: the role of eosinophils and transforming growth factor‐bβ
Authors: Nomura A. , Uchida Y. , Sakamoto T. , Ishii Y. , Masuyama K. , Morishima Y. , Hirano K. , Sekizawa K.
Published: March 2003

Background Collagen type I is one of the major deposits in thickening of the reticular basement membrane of asthma.

Objective and Methods In this study, we assessed turnover of collagen type I in asthma by measuring procollagen type I C‐terminal peptide (PICP) and collagen type I C‐terminal telopeptide (ICTP) in induced sputum.

Results PICP but not ICTP was found to be significantly higher in asthma subjects than in normal volunteers (P < 0.05). In asthma, PICP was inversely correlated with %FEV1.0 (r = −0.539), and its levels significantly increased upon exacerbation (P < 0.05), indicating that collagen synthesis increases during asthma exacerbation. Additionally, PICP was found to significantly correlate with eosinophil counts in sputum (r = 0.539), indicating that eosinophils stimulate collagen turnover. Because eosinophils can produce TGF‐β, a potent stimulator of collagen synthesis, we immunocytochemically examined TGF‐β‐positive cells in sputum. TGF‐β‐positive cells significantly correlated with eosinophil counts (r = 0.811) and PICP (r = 0.569), suggesting that TGF‐β released from eosinophils is involved in collagen synthesis.

Conclusions The results of the present study suggest that collagen synthesis is stimulated in asthmatic airways by eosinophils through TGF‐β, while collagen degradation is not, and that PICP in sputum can act as a new marker for airway inflammation in asthma.
Particulate masks and non‐powdered gloves reduce latex allergen inhaled by healthcare workers
Authors: Mitakakis T. Z. , Tovey E. R. , Yates D. H. , Toelle B. G. , Johnson A. , Sutherland M. F. , O'Hehir R. E. , Marks G. B.
Published: March 2003

Background Although allergy to latex is a well‐characterized phenomenon, some hospitals continue to provide staff with powdered latex gloves as an option to low‐ or non‐powdered gloves.

Objective We aimed to measure the extent to which inhalation of latex particles could be reduced by the use of protective masks or by replacing powdered latex gloves with non‐powdered latex gloves.

Methods Twenty healthcare workers in a hospital setting wore nasal air samplers (NAS) and Institute of Occupational Medicine (IOM) samplers for four 20‐min periods. Subjects wore powdered gloves, non‐powdered gloves and no gloves during three sampling periods, and in the fourth, subjects applied an aerosol barrier face‐mask or a particulate face‐mask (N95) while wearing powdered gloves. All samples were stained for particles bearing Hev b 5 allergen by the Halogen assay.

Results All subjects inhaled Hev b 5 bearing particles in all sampling periods. IOM samplers collected particles at 70% of the rate of NAS. The number of particles inhaled while wearing powdered gloves was 23.8‐fold higher than when not wearing gloves and 9.7‐fold higher than when wearing non‐powdered latex gloves (P < 0.0001). Wearing an aerosol barrier mask did not significantly reduce the number of particles inhaled (P = 0.108), while use of particulate masks significantly reduced the number of particles inhaled by 17.4‐fold (P = 0.003).

Conclusions Use of non‐powdered gloves is the most effective method of reducing occupational aeroallergen exposure to latex arising from gloves. However, secondary protection using particulate masks is a valid alternative, and may be helpful for preventing respiratory sensitization.