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Biomedical subjects

C Rothschild

Publications and source records attributed to C Rothschild.

At least 19 recordsLinked to original sources
PubMed2006

Impact of choice of treatment for bleeding episodes on inhibitor outcome in patients with mild/moderate hemophilia a and inhibitors.

Patients with mild/moderate hemophilia A (MHA) may develop inhibitors to factor VIII (FVIII). In this condition, FVIII clotting activity (FVIII:C) baseline levels may remain stable for some patients, but may be reduced to less than 0.01 U/mL for others. Several risk factors for the development of inhibitors in MHA have been proposed. Genetic factors, such as mutations in the FVIII gene, may play a central role; however, other influences, such as intensive treatment with FVIII products, may also be important. Optimal treatment regimens have yet to be determined, not only for the eradication of inhibitors, but also for the management or surgical prophylaxis of hemorrhages associated with this condition. Several treatment options for the control of bleeding in patients with MHA and inhibitors (MHAI) are currently available, and the choice of therapeutic strategy should be given careful consideration; some treatments may produce an anamnestic response, thus delaying the return to FVIII:C baseline levels and adversely affecting the duration of the severe bleeding phenotype. To increase our knowledge of MHAI, a retrospective collection of data is currently being performed among hemophilia centers in France and Belgium. Based on five examples of patients with MHAI collated from preliminary study data, we illustrate the impact on inhibitor outcome of the therapeutic choices used to treat bleeding episodes in these patients.

Blood Coagulation Factor Inhibitors↗
PubMed2005

Recommendations for postmarketing surveillance studies in haemophilia and other bleeding disorders.

Prospective surveillance studies to monitor drug safety in the postapproval period are rarely employed systematically, although they are of greatest value for caregivers, drug users and regulatory authorities. Safety issues have affected not only conventional pharmaceuticals, but also especially coagulation factors in haemophilia treatment. The reputation of postmarketing surveillance (PMS) studies has been questionable, mainly due to their misuse to solicit prescriptions. Other weaknesses include inappropriate design, lack of standardized observation, limited follow-up periods, absence of rigour in identifying potential adverse drug effects, and infrequent publication. Although well-designed clinical trials represent the gold standard for generating sound clinical evidence, a number of aspects would make PMS studies valuable, if properly conducted. One of their main advantages is broader inclusion, and absence of an 'experimental' design. Lack of proper guidelines, and standardization may constitute a reason for the generally low quality of PMS studies. This paper proposes guidelines for haemophilia-specific PMS studies, in order to improve the acceptance of a basically valuable tool. In the absence of consistent regulatory guidance it will be especially important that the design and supervision of PMS studies involves physicians from the beginning. This will not only make such studies more scientifically relevant, but also help to implement them into daily clinical practice. Specifically in haemophilia, PMS studies may provide valuable data on clinical outcomes, or Quality of Life, which is of great importance when considering adequate standards of care in haemophilia patients.

Blood Coagulation Disorders↗
PubMed2003

Thermodynamic resolution of periosteal reaction and taphonomic change.

New bone formation (e.g., periosteal reaction) is one component of bone and joint disease diagnosis. Its application in the archeologic record has been compromised by lack of standardization. An objective technique for validating observations seems especially valuable when visual examination of a single data set results in widely disparate perspectives. Such discrepancies as to presence or absence of periosteal reaction are amenable to objective analysis. Bone, as any other form of matter, has a variety of properties. Some are characterized by weight or volume and are referred to as colligative. Some are related to its intrinsic nature, independent of mass. The latter are referred to as non-colligative. Non-colligative properties of matter provide an opportunity to assess structure, independent of quantity. Study of one such property, entropy, revealed that taphonomic changes can confidently be distinguished from bone surface reaction. Contrasted with the homogeneous entropy of normal bone, the loss of surface bone inherent in taphonomy results in reduced entropy. Contrasted with the homogenous patterns of normal bone, specific non-homogenous patterns allow periosteal reaction to be recognized, independent of variety of periosteal reaction or its origin. Thermographic approach allows observational techniques to be independently validated. Such validation allows for greater facility in interobserver archeologic site sample comparisons.

Bone Remodeling↗
PubMed2002

European data of a clinical trial with a sucrose formulated recombinant factor VIII in previously treated haemophilia A patients.

To increase the safety of antihaemophilic treatment, the production process of full-length recombinant factor VIII (FVIII) KOGENATE Bayer (Kogenate FS) has been modified. Human albumin is no longer added as stabilizer during purification and in final formulation. Instead, the new KOGENATE Bayer production process uses sucrose as a stabilizer in the formulation and adds solvent/detergent virus inactivation step. An European clinical trial was carried out in Germany and France in previously treated patients with severe haemophilia A who had more than 100 exposure days to exogenous FVIII. Pharmacokinetic data was analysed according to one-stage and chromogenic assays. Efficacy and safety during home therapy and in surgical procedures were evaluated; inhibitor formation was carefully monitored. Safety and efficacy were evaluated in 33 European patients for 24 months. Patients received more than 13 million IU KOGENATE Bayer. Over 75% of patients accrued more than 100 exposure days with the new product. Of 875 bleeding episodes, 90.7% were treated with 1 or 2 infusions and 75.8% of responses to treatment were rated as 'excellent' or 'good'. Prophylactic treatment was the most common mode of therapy (60.7% of infusions). The product was well-tolerated and FVIII recovery studies were consistent throughout the study period. Only 0.26% of adverse events were reported to be drug related. No evidence of de novo inhibitor formation was observed. Overall, KOGENATE Bayer was efficacious, safe and well-tolerated for the treatment of haemophilia A in multitransfused patients.

Adolescent↗
PubMed2002

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.

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. This modified one-stage method may therefore offer an alternative to the use of a concentrate-specific standard.

Chromogenic Compounds↗
PubMed2001

The French haemophilia cohort: rationale and organization of a long-term national pharmacosurveillance system.

Medicinal products of biological origin still carry a specific iatrogenic risk, mainly because of their starting material, mode of preparation and variability. Careful postmarketing surveillance systems are therefore necessary. To assess the long-term safety of haemophilia treatment with plasma-derived and recombinant clotting factor products, a cohort study was set up in France in 1994. Participants were patients with haemophilia A and B, with or without previous clotting factor therapy. Clinical events, treatments, biological data and adverse events were recorded on standard forms. Blood samples were separated into serum, plasma and peripheral blood mononuclear cells, frozen, and banked in a central laboratory. The same data and samples were collected at yearly follow-up visits. As of December 1999, 1234 haemophiliacs were enrolled in 39 haemophilia centres. At enrollment, 50.2% of patients were under 15 years of age, and the cumulative number of days of exposure to the product was below 50 in 35.1% of cases. The median duration of follow-up was 26.9 months, with a total of 2729 patient-years (135,947 days of exposure and 211 million units of factor VIII or IX). To date, only 17 patients were lost to follow-up. The initial results show good compliance with this health-watch policy among patients and clinicians specializing in haemophilia. The regular follow-up data and centralized sample bank will serve to investigate rapidly any suspected outbreaks as soon as reliable biological tests become available in the future.

Adolescent↗
PubMed2001

Skeletal manifestations of leprosy: analysis of 137 patients from different clinical settings in the pre- and post-modern treatment eras.

This study was conducted to further characterize the nature of leprosy-related bone alterations, to develop a hypothesis of their pathophysiology, and to define the impact of treatment on bone damage. Radiographs of 60 patients under care at the Carville, Louisiana leprosy hospital were compared with 50 from the early (before availability of effective treatment) part of this century and with 27 from the Toronto (Ontario, Canada) leprosy clinic. Two-thirds of lesions were so severe that distal digital tufts had been lost to whittling, resorption, or fragmentation. Fifty percent were felt to be pathognomonic for the changes of leprosy. Resorption, fragmentation, and malaligned fractures are highly suggestive of leprosy, while diaphyseal whittling appears specific when medullary sclerosis or wavy diaphyseal borders are present. Medicinal intervention appeared to be of limited benefit for bone damage; perhaps greater attention to joint/bone protection (as recommended in diabetes management) will prove helpful. Environmental adjustment to minimize injury risk and daily limb examination for injury are recommended.

Journal Article↗
PubMed2001

Inflammatory arthritis in canids: spondyloarthropathy.

Spondyloarthropathy was observed in 25 (2.8%) of 895 preserved canid museum specimens and was catalogued by species. The associated skeletal alterations in canids are indistinguishable grossly and physiologically from those in humans with spondyloarthropathy of the reactive type. Rate of affliction was independent of captive or wild-caught status or gender. In canids, spondyloarthropathy was much more common than osteoarthritis (0.3%), which predominantly is limited to captive animals. Animal well-being may be enhanced by recognition of the condition and initiation of specific treatment.

Animals↗
PubMed2000

First European exposure to syphilis: the Dominican Republic at the time of Columbian contact.

Recognition of syphilis in Europe in the late 15th century and its prior absence suggest New World origin. Skeletal populations were examined from sites with documented Columbian contact in the Dominican Republic. Examination of 536 skeletal remains revealed periosteal reaction characteristic of treponemal disease in 6%-14% of the afflicted population. Findings were identical to that previously noted in confirmed syphilis-affected populations and distinctive from those associated with yaws and bejel: it was a low population frequency phenomenon, affecting an average of 1.7-2.6 bone groups, often asymmetric and sparing hands and feet, but associated with significant tibial remodeling. While findings diagnostic of syphilis have been reported in the New World, actual demonstration of syphilis in areas where Columbus actually had contact was missing, until now. The evidence is consistent with this site as the point of initial contact of syphilis and of its subsequent spread from the New World to the Old.

Bone and Bones↗
PubMed2000

Laboratory aspects of rheumatologic disease.

Assessment of laboratory values is an important function of nursing practice. Rheumatologic laboratory assessment, in particular, can be complex because few findings are actually pathognomonic. This article provides a perspective on an interpretive approach to laboratory assessment of rheumatologic disease. In conjunction with the patient's clinical status, these values can provide helpful information for monitoring or predicting the course of disease.

Acute-Phase Proteins↗
PubMed2000

Mapping and functional studies of two alloantibodies developed in patients with type 3 von Willebrand disease.

Inhibitors against von Willebrand factor (vWF) developed in two unrelated multitransfused patients (patients 1 and 2) with severe (type 3) von Willebrand disease (vWD) were analyzed. Both inhibitors were identified as antibodies of the IgG class by ELISA using immobilized purified vWF and either serum or purified Ig from the patients. Typing, mapping and functional studies of both antibodies revealed significantly distinct properties. Patient 1 antibody contained all subclasses of IgG (1, 2, 3 and 4) whereas antibody from patient 2 was a mixture of only IgG1 and 4. By ELISA using a series of immobilized purified proteolytic fragments of vWF, patient 1 antibody mainly bound to fragment SpIII and, to a lower extent, to fragments SpII and SpI; it poorly bound to P34 and the 39/34 kDa fragment. In contrast, patient 2 antibody only bound to fragments corresponding to the N-terminal portion of vWF but failed to bind to SpII. Functional studies were performed by testing the capacity of each antibody to inhibit vWF binding to its various ligands. Both antibodies blocked vWF binding to Factor VIII (FVIII), fibrillar type III collagen, bitiscetin and the subsequent induced binding to GPIb. Patient 1 antibody also blocked vWF binding to platelet GPIb when induced by ristocetin. However it failed to block vWF binding to GPIb when induced by botrocetin as well as the binding of botrocetin itself to vWF. Our data thus suggest that this inhibitor does not recognize the GPIb-binding site on vWF but the sites of vWF involved in its interaction with ristocetin. In contrast, we observed that patient 2 antibody blocked vWF binding to platelet GPIb induced by either agonist as well as vWF binding to botrocetin. Finally, the effect of the antibodies was tested on vWF binding to GPIIb/IIIa. As expected from the mapping experiments, only IgG from patient 1 blocked the interaction while IgG from patient 2 had no effect. In conclusion, we have shown that two multitransfused patients with type 3 vWD have developed alloantibodies with similar properties to those of polyclonal antibodies but with distinct effects on the functions of vWF.

Adult↗
PubMed1999

[The young hemophiliac, inhibitors and immune tolerance].

The occurrence of inhibitor in a hemophilic patient is the greatest therapeutic complication in 1999. The inhibitor incidence is higher in hemophilia A (20-30%) than in hemophilia B (3%). At the moment, the best management is immune tolerance induction. This consists in frequent infusion of antihemophilic factor (every day or every other day). The risk of inhibitor development is higher in a young child than in an adult. Consequently, a venous access device is essential for this treatment although not devoid of complications in the young boy. Moreover, the probability of inhibitor disappearance is higher in a child (recent inhibitor) than in an adult ("old" inhibitor).

Adult↗
PubMed1999

Incidence of factor IX inhibitor development in severe haemophilia B patients treated with only one brand of high purity plasma derived factor IX concentrate.

Fifteen previously untreated patients (Pups) with severe haemophilia B (factor IX activity < or = 2 U/dl) only treated with one brand of plasma-derived high purity factor IX concentrate (FIX LFB) were studied. Age at first injection varied from 1 to 137 months and follow-up since this first injection from 21 to 86 months (median: 35). Cumulative exposure days (CED) were from 4 to over 100 (median: 26). Among these 15 Pups only one developed an inhibitor. Mutation analysis performed in all patients showed total gene deletion in the patient with inhibitor, partial gene deletion in another one, and missense mutations in 9 families. Mutation was not found in one patient. Actually, according to the data already published, only two patients were at high risk for inhibitor development in our population. Our study, although rather small, confirms the previously reported low incidence of inhibitors in haemophilia B. Large studies on incidence of FIX inhibitors are indeed difficult to perform, due to both the overall small number of severe haemophilia B patients and the low incidence of FIX inhibitors. Consequently, the impact of bias, such as prevalence of different types of gene defects in a given population, is major. Therefore, any study, dealing with incidence of FIX inhibitors in severe haemophilia B should report, for each patient, the type of gene defect.

Antibodies↗
PubMed1998

[Willebrand disease].

Von Willebrand disease is the most frequent congenital bleeding tendency (1%). The moderate form is the most common (around 80%). It must consistently be investigated prior to any surgery because of a real risk of bleeding during or after the procedure. Once the diagnosis is made, the indication of DDAVP has to be examined in order to make the best therapeutic choice in case of surgery or severe bleeding.

Diagnosis, Differential↗