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Biomedical subjects

J M Lusher

Publications and source records attributed to J M Lusher.

At least 19 recordsLinked to original sources
PubMed1992

Effect of age on human immunodeficiency virus type 1-induced changes in lymphocyte populations among persons with congenital clotting disorders. Transfusion Safety Study Group.

Children other than neonates infected with human immunodeficiency virus type 1 (HIV-1) have low rates of progression to acquired immunodeficiency syndrome (AIDS). Through 1989, 5.3% of 95 infected hemophiliacs aged 5 to 13 years developed AIDS, compared with 20.3% of 364 aged greater than or equal to 25 years. We asked whether the HIV-1 impact on peripheral blood mononuclear cell subpopulations differed with age using pairwise comparisons of uninfected and infected male children and adult hemophiliacs. Infected children had lesser reductions of total lymphocytes than adults, but proportionately lower numbers of CD2+, CD4+, CD2+CD26+, and CD4+CD29+ counts. CD4+CD45RA+ cell counts were greater than twofold higher in uninfected and infected children than adults; with infection, the CD4+CD45RA+/CD4+ proportion increased by 1.4-fold in adults, but was unchanged in children. Infected adults had highly significantly increased total CD8+ counts; both age groups had elevated CD8+HLA-DR+ counts. Infected children had significantly higher total B-cell counts than infected adults, with a disproportionately lower number of resting B cells (CD20+CD21+). During 2 years of follow-up, infected children and adults had lymphocyte changes in the same directions and these were proportionately equal. The lower rate of HIV-1 progression in children may be partly associated with differences in lymphocyte populations compared with adults; functional properties of immune cells may be equally or more important.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Variability in serial CD4 counts and relation to progression of HIV-I infection to AIDS in haemophilic patients. Transfusion Safety Study Group.

OBJECTIVE--To examine the CD4 count and its near term changes relative to progression to AIDS within 30 months and to subsequent CD4 counts. DESIGN--Longitudinal clinical and laboratory study. SETTING--Haemophilia treatment centres in six large American cities. PATIENTS--555 people with congenital clotting disorders who were infected with HIV, initially without AIDS, and seen at follow up for 6-30 months in 1986-9. MAIN OUTCOME MEASURES--Absolute CD4 counts and incidence of AIDS. RESULTS--Outset CD4 count and age were independently related to progression to AIDS (p less than 0.0001 and p less than 0.005 respectively). Patients with CD4 counts of 0.30-0.49 x 10(9) cells/l had an age adjusted risk of AIDS within 30 months of only 9% that of patients with counts less than 0.20 x 10(9)/l. Children under 10 years old had only 16% of the CD4 adjusted risk of AIDS of people aged greater than or equal to 45 years. Analysis of 149 patients' CD4 counts at the beginning and end of two successive six month intervals showed an average decrease of 11% in each six months regardless of the outset count (greater than or equal to 0.20 x 10(9)/l). For individual patients the decrease in the second six month period was unaffected by the decrease in the first six month period. CONCLUSIONS--Antiviral treatment of asymptomatic people, particularly children, with CD4 counts greater than or equal to 0.3 x 10(9)/l is questionable if predicted on near term progression to AIDS. Because of individual CD4 count variability and the low rate of progression to AIDS near term declines in individual CD4 counts are a poor index for identifying people who will rapidly progress to AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Hemophilia A.

Over the past few years considerable progress has been made in elucidating the molecular genetics of hemophilia A, in carrier detection and prenatal diagnosis, and in the production of safer clotting factor concentrates. Recombinant FVIII, shown to be safe and effective in ongoing prelicensure clinical trials that began in the spring of 1987, should soon be licensed and commercially available. There is now considerable interest in beginning prophylactic therapy regimens at 1 or 2 years of age, in an attempt to prevent chronic joint disease and other complications of serious bleeding episodes. The possibility of gene insertion therapy for persons with hemophilia now seems to be a realistic one--perhaps achievable in the 1990s. Although many problems remain--major problems resulting from HIV, HCV, and HBV infections; how to deal with existing musculoskeletal problems; how to pay for the higher-priced new technologies; high titer inhibitors; just to name a few--the many recent scientific advances and their clinical applications make this an exciting time. This is truly, as indicated in the title of the proceedings of the XIX Congress of the World Federation of Hemophilia, a new decade of hopes and challenges.

Child, Preschool↗
PubMed1991

Perspectives on the use of factor IX complex concentrates in the treatment of bleeding in persons with acquired factor VIII inhibition.

In contrast to the type of bleeding encountered in congenital hemophilia with inhibitors, the diathesis toward bleeding exhibited by patients with spontaneously acquired factor VIII (FVIII) inhibitors often is severe and life threatening. Large hematomas and retropharyngeal or central nervous system hemorrhage may appear suddenly. Thus, a high premium is placed on rapid therapeutic intervention. Several treatment options are at the physician's disposal. The role of factor IX (FIX) complex concentrates, both standard and purposely activated, is discussed. The FIX products are also known as prothrombin complex concentrates (PCCs). Prudent choice of any treatment modality requires weighing its benefits and shortcomings. Advantages of PCCs--particularly the activated products--include availability, ease of reconstitution and administration, and at least partial efficacy; control of bleeding episodes can be achieved with PCCs in many (but not all) instances. One salient disadvantage of therapy with FIX complex concentrates is that they are not subjected to such rigorous viral-attenuation processes as are most of the currently marketed FVIII products. Therefore, a small but definite risk of infection with hepatitis B or C (HBV, HCV) remains. An assay that detects antibodies against HCV has been licensed and is being used to screen blood donors. Nevertheless, up to the present time the U.S. Food and Drug Administration (FDA) has ruled that HCV screening of plasmapheresis donors should not be performed for plasma collections destined to be pooled for fractionation and that units of HCV-positive source plasma (e.g., that provided by American Red Cross donors) found to be HCV positive be sent for fractionation. The starting plasma from which FIX complex concentrates and human FVIII concentrates are made thus contains some HCV and may also contain some HBV. Because nonhemophiliacs with acquired antibodies against FVIII are unlikely to have had prior exposure to blood products and are unlikely to have been vaccinated against HBV, they are at risk of viral hepatitis and its sequelae when treated with FIX complex concentrates. Furthermore, therapy with FIX complex concentrates is not always effective in controlling bleeding in persons with FVIII inhibitors, its mechanism of action in bypassing the need for FVIII remains unclear, very large doses are required, and it has an attendant risk of several adverse effects when used in large, repeated doses. These include disseminated intravascular coagulation, thromboembolism, and acute myocardial infarction. Thus, FIX complex concentrates may play a useful role in the treatment of bleeding in nonhemophiliacs with acquired inhibitors against FVIII, but one must carefully consider their disadvantages profile.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoantibodies↗
PubMed1991

The problem of therapeutic equivalence with paired qualitative data: an example from a clinical trial using haemophiliacs with an inhibitor to factor VIII.

The problem of demonstrating the equivalence of two treatments or drugs occurs fairly frequently in medicine, but is quite often misformulated. The common error is to assume equivalence is demonstrated if the usual null hypothesis of no difference is not rejected, which ignores the potential of a substantial beta-error. We describe here two procedures for testing equivalence when the data are paired and dichotomous, and provide sample size formulas. We give an example based on a clinical trial of haemophiliacs with inhibitor to Factor VIII.

Antibodies↗
PubMed1991

Hemophilia.

Explore the source record for details and available documents.

Adolescent↗
PubMed1991

Risk of human immunodeficiency virus type 1 infection among sexual and nonsexual household contacts of persons with congenital clotting disorders.

The status of human immunodeficiency virus type 1 (HIV-1) infection at the time of transmission to sexual contacts remains poorly defined. Transmission to nonsexual household contacts has appeared to be rare. A total of 505 sexual and nonsexual contacts of HIV-1-infected hemophiliacs in 349 households was observed. At entry, 10% of 201 sexual partners were anti-HIV-1-positive. Follow-up of 151 uninfected partners during a total of 351 person-years of observation showed no sero-conversions, although there were 13 pregnancies during that period. Eighty-seven percent of the seronegative respondents to a detailed questionnaire reported unprotected sexual contact at least occasionally. Among 304 other household members, including 108 parents who helped administer clotting factor concentrates to their children, none was seropositive at entry. Follow-up of 263 showed no seroconversions during a total of 605 person-years of observation. Thus, anti-HIV-1-positive hemophiliacs transmitted to their partners earlier in their course but were not found to do so when prospectively observed. No relationship to level of viremia as indicated by CD4 count, HIV-1 p24 antigenemia, or acquired immunodeficiency syndrome was found. Anti-HIV-1-positive hemophiliacs had not transmitted to their nonsexual household contacts before study entry and did not do so subsequently, indicating that the risk from even close nonsexual contact is extremely low.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Retrovir therapy in hemophilic children with symptomatic human immunodeficiency virus infection: efficacy and toxicity.

In desperation, we have used retrovir in five hemophilic children (10-16 years old) over the past 22 months. All had presented with various clinical manifestations of acquired-immune-deficiency-syndrome (AIDS)-related complex or AIDS. Our decision to treat with retrovir was based on clinical manifestations and very low numbers of CD4 cells (less than 200). The most common clinical presentation was recurrent oral moniliasis. Other significant findings included recurrent herpes zoster, thrombocytopenia, growth failure, and biliary tract infection. Initially, all five children received the full adult dosage of retrovir (200 mg q 4 h x 6 doses/day). This dosage had to be reduced in four children because of toxicity. The most commonly observed toxic side effects were anemia and neutropenia. Alanine aminotransferase (ALT) levels rose to 4-10 times the upper limit of normal in four of five children. One was on concomitant ketokonazole prior to the rise in ALT level. Myalgia and headache were reported by two patients. Improvement in clinical and immunological status was observed in all children initially. After 12-18 months of retrovir therapy, infectious complications secondary to prolonged neutropenia were seen in these immunocompromized children. However, compared to historic controls, these children have had fairly stable disease. We feel that all hemophilic children with symptomatic human immunodeficiency virus infection should be offered this drug, even though the optimal dosage for children is not yet established.

AIDS-Related Complex↗
PubMed1990

Transmission of human immunodeficiency virus type 1 by dry-heated clotting factor concentrates. Transfusion Safety Study Group.

The Transfusion Safety Study monitored susceptible persons for human immunodeficiency virus type 1 (HIV-1) infections transmitted by plasma products and blood components. Through December, 1988, 6 subjects without antibody to HIV-1 (anti-HIV-1) became seropositive after receiving dry-heated factor VIII concentrate. The preparations implicated in 3 cases were derived entirely from anti-HIV-1-screened donors. In all instances, HIV-1 infection could be explained by concentrates heated at 60 degrees C for 24-30 h. Limiting consideration to concentrates and components administered after study entry showed that 4 of the seroconversions occurred among 122 subjects given 10 million units of factor VIII concentrates. No seroconversions occurred among 84 subjects given 5 million units of factor IX concentrates, or 83 who received components from over 26,000 unpaid donations. Serologic surveillance of anti-HIV-1-negative subjects provides important information, and should be routine in the management of persons receiving clotting factor concentrates.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Viral safety and inhibitor development associated with factor VIIIC ultra-purified from plasma in hemophiliacs previously unexposed to factor VIIIC concentrates. The Monoclate Study Group.

A multicenter study evaluated the potential for transmitting non-A/non-B hepatitis, as well as other viruses, with the use of the factor VIIIC product Monoclate. This product is purified from plasma via the monoclonal process that includes heat treatment for ultra-purification as a final step. Twenty different lots of Monoclate were used, and each patient received the assigned lot for the first 6 months of the trial. Nineteen of 38 patients adhered strictly to International Committee on Thrombosis and Hemostasis criteria in that they had normal liver enzymes, no evidence of hepatitis prestudy, and had no previous blood product use. Fourteen hemophilia centers from the United States, the United Kingdom, the Netherlands, and Israel participated in this study. Development of factor VIII inhibitor occurred in six of 38 patients, which was within the statistically expected range. Adverse events were mild, and Monoclate was well tolerated in this group. All 38 patients remained HIV seronegative.

Alanine Transaminase↗
PubMed1990

Initial clinical experience with a new pasteurized monoclonal antibody purified factor VIIIC.

Heat treatment of lyophilized factor VIII and factor IX concentrates has been found to eliminate HIV virus infectivity in plasma-derived products. Pasteurization of factor VIII in solution has recently been used to reduce the risk of hepatitis transmission in concentrates prepared by standard fractionation methods. This report presents early experience with factor VIIIC prepared by monoclonal antibody immunoaffinity chromatography following pasteurization of the factor VIIIC/von Willebrand factor complex (Monoclate-P). Twelve patients were treated in three centers with Monoclate-P. Recovery and survival of factor VIII clotting activity were determined and patients were closely monitored for infusion safety. The mean half-life was 14.2 +/- 5.0 while recovery in predicted plasma volume was 72 +/- 12% corresponding to a response of 1.99 +/- 0.66 U/dL for every U/kg administered. These values are very similar to those found for Monoclate in previous studies indicating that pasteurized factor VIIIC purified by immunoaffinity chromatography retains satisfactory pharmacokinetic properties with an added margin of viral safety.

Adolescent↗
PubMed1986

Intravenous gammaglobulin (Gaminume) for treatment of chronic idiopathic thrombocytopenic purpura (ITP): a two-year follow-up.

Thirteen subjects 5-20 years of age with the chronic, autoimmune form of idiopathic thrombocytopenic purpura (ITP) were given intravenous gammaglobulin (Gamimune; Cutter Biological, Berkeley, CA) in a dose of 400 mg/kg per day for 5 consecutive days. Two of the 13 children had undergone splenectomy; the other 11 had not. Eight of these 13 children had also received corticosteroid therapy with no sustained increase in platelet counts. Six of 13 children had a good or excellent response to the first 5 day course of gammaglobulin therapy, and one had a fair response. The peak platelet count occurred within 7 days of the start of therapy except in one patient, whose platelet count peaked on day 12. Six of seven patients who initially responded to Gamimune required booster doses to maintain platelet counts at a safe level. All children had marked increases in serum IgG following Gamimune except one (who had undergone splenectomy for chronic ITP), who had high baseline levels of immunoglobulin G (IgG). No untoward reactions necessitating cessation of therapy were encountered during this study. The most common side effect observed was headache. During the first year of follow-up after Gamimune, three of seven initial responders became refractory to Gamimune therapy. Two of these three refractory subjects later underwent splenectomy with excellent response. The third refractory patient who was splenectomized prior to gammaglobulin therapy had spontaneous remission of his ITP 5 months after the last dose of Gamimune. Three of the four other initial responders have continued to do well and have maintained platelet counts above 40,000/mm3 (one without booster). The fourth subject dropped out of the study. Thus our observations indicate that Gamimune is an effective form of treatment for some children with chronic ITP, and can be considered as an alternative to splenectomy or as a potential therapeutic modality in those who have failed to respond to splenectomy.

Chronic Disease↗
PubMed1979

Erythropoiesis in sickle cell anaemia during acute infection and crisis.

Erythropoiesis was evaluated in 37 patients with sickle cell anaemia, 26 of them children under 12 years of age. Mean haemoglobin, haematocrit, reticulocyte, and erythropoietin levels were similar for 11 who were asymptomatic, 11 with infections, and 12 in vaso-occlusive crisis. Mean haemoglobin, haematocrit, and reticulocyte values were significantly lower and the mean erythropoietin level significantly higher for three patients in aplastic crisis. Reticulocyte counts reflected erythropoietic activity during the asymptomatic state but were variable during infection and crisis. No erythropoietic inhibitory activity was found in any of the four clinical states. It has been suggested that erythropoietin production decreases during infection. Patients in this study responded appropriately to stress, showing no decrease in erythropoietic activity during acute infection or crisis.

Adolescent↗
PubMed1979

Structural physiology of the human spleen.

The structural physiology of the human spleen is discussed in depth here, with particular emphasis on the interrelationships between blood cells and the spleen. The unique microvasculature and structural relationships of the spleen form the basis for a number of functions important in both health and disease. Utilizing scanning electron microscopy one can visualize the interactions between blood elements and the spleen---the passage of deformable erythrocytes through narrow slits in the endothelium separating cord and sinus, the trapping of less deformable cells in the cords, the culling and pitting of abnormal or inclusion-bearing erythrocytes by splenic macrophages, as well as the sites of interaction between antigenic stimuli such as pneumococcal organisms and the T and B cells of the spleen.

Anemia, Hemolytic↗