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Biomedical subjects

C M Kessler

Publications and source records attributed to C M Kessler.

At least 55 records · Page 3Linked to original sources
PubMed1995

Randomized study of didanosine monotherapy and combination therapy with zidovudine in hemophilic and nonhemophilic subjects with asymptomatic human immunodeficiency virus-1 infection. AIDS Clinical Trial Groups.

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.

Adult↗
PubMed1995

Coagulant proteins and thrombin generation in synovial fluid: a model for extravascular coagulation.

The coagulant content and thrombin generating potential of synovial fluid from patients with osteoarthritis were studied as a model of extravascular coagulation. The concentrations of individual coagulant proteins were partially correlated with their molecular weight. The levels of the very large coagulants factor V, factor VIII and von Willebrand factor antigen (vWF:ag) are less than 1% of the activities found in a normal pooled reference plasma while smaller coagulants including factors IX, XI and prothrombin range between 9 and 30%. The protease inhibitors antithrombin-III (AT-III) and Alpha-2 macroglobulin in synovial fluid were present at levels of 74% and 13% of plasma, higher than expected based on their molecular weights. Prothrombin was more rapidly activated by tissue thromboplastin than by aPTT reagent. The thrombin activity formed in synovial fluid decreased more rapidly than that formed in dilute plasma. The addition of recombinant factor VIII or bovine factor V to synovial fluid accelerated the thrombin production by APTT but not by tissue thromboplastin. Indicating that the low levels of factor VIII and factor V did limit the rate of thrombin production. The addition of specific antibodies to factor VIII or factor V strongly inhibited thrombin production by aPTT. These data confirm a roughly inverse relationship between the concentrations of coagulation proteins and their molecular weight in synovial fluid and indicate that thrombin can be generated in synovial fluid. The inactivation of thrombin in synovial fluid may be more dependent on antithrombin-III than in plasma because of the increased AT-III/alpha-2 macroglobulin ratio seen in synovial fluid.

Animals↗
PubMed1995

Treatment of inherited coagulation disorders.

Inherited coagulation protein deficiencies associated with bleeding diatheses may present with spontaneous bleeding early in life, or may not be recognized until the development of hemorrhage after trauma or surgery. Diagnostic evaluation with coagulation screening tests, followed by confirmation with coagulation factor assays, is essential for appropriate management. For moderate-to-severe hemophilia, treatment includes coagulation factor replacement with purified, plasma-derived coagulation factor, or in the case of hemophilia A, factor VIII concentrate produced with recombinant techniques. Increased use of pharmacologic agents such as desmopressin acetate for patients with mild hemophilia A or type 1 von Willebrand's disease has allowed physicians to treat patients without the risk of infectious complications from plasma-derived factor concentrates. In addition to the management of the inherited bleeding disorders, patients may also require management of human immunodeficiency virus infection, hepatitis, and coagulation factor inhibitors. Issues for the coming years will include continued work to ensure product safety, the role of prophylactic treatment to prevent longterm disabilities, and the application of gene therapy to the management of bleeding disorders.

Blood Coagulation Disorders↗
PubMed1995

Total knee arthroplasty in human immunodeficiency virus-infected hemophiliacs.

Twenty-six knee arthroplasties were performed in 15 patients with hemophilia A and human immunodeficiency virus infection from 1984 to 1991. Patient age range was 27 to 48 years. After an average follow-up period of 6.4 years (range, 1-9 years) all patients were alive and none of the implants had become infected. T4 lymphocyte counts showed some deterioration, which was not clinically significant. All of the patients were improved following surgery. Nineteen implants were rated excellent, four good, and three fair. Infection with human immunodeficiency virus did not adversely affect the clinical outcome of knee arthroplasty at follow-up periods up to 9 years.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Monitoring the anticoagulant effects of a low molecular weight heparin preparation. Correlation of assays in orthopedic surgery patients receiving ardeparin sodium for prophylaxis of deep venous thrombosis.

This prospective, uncontrolled trial explored the relationship between varying dosages of a low molecular weight heparin (LMWH) preparation, ardeparin sodium (Normiflo, Wyeth-Ayerst, Philadelphia, PA), and anticoagulant effects, monitored by an amidolytic anticoagulation factor Xa (aXa) assay and by global coagulometric methods, including the activated partial thromboplastin time (APTT) and the Heptest (Haemachem, St. Louis, MO). Thirty-three patients undergoing elective unilateral total hip or knee replacement received subcutaneous ardeparin prophylaxis initiated 12 to 18 hours following surgery, administered at a fixed 40-mg dose twice daily, 50 aXa U/kg twice daily or 90 aXa U/kg once daily for up to 14 days. The target antithrombotic aXa levels, determined by amidolytic assay in plasma 6 hours after each ardeparin injection, were most optimally attained and maintained by twice-daily dosing based on body weight and correlated well with incremental increases in Heptest values measured chronometrically. The Heptest results at 12 hours after ardeparin administration indicated that the global anticoagulant effects produced by LMWH are sustained for many hours after subcutaneous dosing.

Anticoagulants↗
PubMed1995

Human immunodeficiency virus (HIV) type 1 infection status and in vitro susceptibility to HIV infection among high-risk HIV-1-seronegative hemophiliacs.

Blood samples were obtained from 16 hemophiliacs who had a 50%-94% defined risk of human immunodeficiency virus (HIV) type 1 infection on the basis of treatment history and from 14 controls not at risk for HIV infection. HIV-1 was not detected in any of 12 patient samples by cocultivation nor in 14 patient samples by the polymerase chain reaction. Peripheral blood cells from 7 seronegative hemophiliacs at highest risk of seroconversion (94%) were less susceptible to HIV-1 infection in vitro than were cells from healthy controls (P < .025, one-tailed Wilcoxon rank sum test). In contrast, the susceptibility to HIV-1 infection of lymphocytes from 6 seronegative hemophiliacs at moderate risk (50%-56%) of seroconversion did not differ from that of cells from controls or from high-risk hemophiliacs. Therefore, prolonged periods of seronegative HIV-1 infection are not common in this high-risk population. In addition, among hemophiliacs there may exist heterogeneity in susceptibility to HIV-1 infection in vitro and in vivo.

Adult↗
PubMed1995

Distribution and correlates of plasma fibrinogen in middle-aged women. Initial findings of the Postmenopausal Estrogen/Progestin Interventions (PEPI) study.

Fibrinogen levels have been reported in cohort and case-control studies to be positively related to the development of coronary heart disease. This report presents the distribution and determinants of fibrinogen in women enrolling in a 3-year randomized trial of hormone replacement therapy (HRT), the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. Fasting plasma fibrinogen levels were measured in 874 postmenopausal women, aged 45 to 65 years, who had not used HRT for at least 3.5 months. Mean (+/- SD) fibrinogen level was 2.83 +/- 0.45 g/L. There was a significant positive association between fibrinogen and age (P = .03). Significantly higher (P < .005) fibrinogen levels were seen in current smokers versus nonsmokers (2.94 versus 2.81 g/L), in women who reported consuming fewer than 12 alcoholic drinks in the 12 months before the baseline visit versus higher consumption (2.90 versus 2.79 g/L), and in women who reported never versus ever having used HRT (2.90 versus 2.77 g/L). Self-reported leisure time physical activity (LTPA) was negatively associated (P = .0001) with fibrinogen levels as follows: inactive (2.84 g/L), light (2.89 g/L), moderate (2.80 g/L), and heavy (2.60 g/L), with significantly (P = .0001) lower levels in women who reported heavy LTPA versus each of the other categories and in women reporting moderate versus light LTPA. A strong positive correlation was found between fibrinogen and body mass index (BMI) (r = .32; P < .0001). In a model that included age, smoking, alcohol intake, prior HRT, LTPA, and BMI, LTPA was no longer a statistically significant predictor of fibrinogen level, while associations with other variables remained significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Risks of immunodeficiency, AIDS, and death related to purity of factor VIII concentrate. Multicenter Hemophilia Cohort Study.

In HIV-infected subjects with haemophilia, CD4 counts seem to fall more slowly in those on high-purity factor VIII (FVIII) than on intermediate-purity product. We evaluated whether risks for AIDS or death were associated with either product among 411 HIV-infected individuals. The relative hazard of AIDS was slightly elevated for both current (1.34) [corrected] and cumulative (1.01 per month) use of high-purity products (neither significant). The corresponding hazards for death were 1.49 and 1.03 (neither significant). Thus we found no evidence that high-purity FVIII concentrates retard the development of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Platelet thromboembolism.

Platelet-dependent thrombosis and subsequent embolization are major causes of cerebral ischaemia. Beside aspirin which irreversibly blocks platelet cyclo-oxygenase, several other substances interfere in different platelet metabolic pathways and block platelet adhesion and aggregation. We found in an experimental model using non-human primates that a specific peptide inhibitor blocking GP IIb/IIIa platelet receptor which binds fibrinogen completely, prevents the retention of embolized platelet aggregates in the cerebral circulation. As thrombin may play a key role for platelet activation in vivo leech-derived hirudin, a direct thrombin inhibitor as well as activated protein C which limits thrombin production and also prevents platelet dependent thrombus formation very effective. We demonstrated in the same non-human primate model of platelet embolization that the amount of retention of platelet emboli in the vascular bed depends on the nature of the vasculature. For example, platelet emboli were cleared very quickly from brain microcirculation, whereas platelet embolization into the lower limb via the femoral artery caused a significantly longer retention of the embolized material. Such specific mechanisms may be caused by different levels of local vasodilators as PGI2 or EDRF.

Animals↗
PubMed1993

Carotid artery disease in vascular ocular syndromes.

We prospectively investigated 83 consecutive patients with vascular ocular syndromes: 19 suffered from amaurosis fugax attacks, 23 had occlusions of the central retinal artery or a branch retinal artery occlusion, 26 had a central retinal vein occlusion or a branch retinal vein occlusion, and another 15 exhibited an anterior ischemic optic neuropathy. In 5 patients bilateral symptoms occurred; thus a total of 88 eyes were affected. All patients underwent a neurological examination and ultrasound investigations of the carotid arteries, including continuous wave (cw)-Doppler-sonography and duplex ultrasound. Stenosis of more than 50% diameter reduction and occlusion of the internal carotid artery ipsilateral to the symptomatic eye were significantly more frequent in amaurosis fugax attacks and central or branch retinal artery occlusion than in central or branch retinal vein occlusion or anterior ischemic optic neuropathy (p < .025). Additionally, the analysis of plaque surface and echogenicity of the plaques on the affected side with a high-resolution duplex scan uncovered that ulcerated plaque surfaces and plaques with a heterogeneous echogenicity were found significantly more frequent in the internal carotid arteries of patients with amaurosis fugax attacks and central or branch retinal artery occlusions than in patients with anterior ischemic optic neuropathy (p < .04) or central and branch retinal vein occlusion (p < .025). We conclude that amaurosis fugax attacks and central retinal artery or branch retinal artery occlusions are due to arterio-arterial embolization from ulcerated and heterogeneous carotid artery plaques.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Incidence of lymphomas and other cancers in HIV-infected and HIV-uninfected patients with hemophilia.

OBJECTIVE: To determine the types and rates of cancers occurring in excess in the presence of infection with the human immunodeficiency virus type 1 (HIV-1). DESIGN: Cohort analytic study of HIV-infected and HIV-uninfected subjects followed for up to 12 years. SETTING: Fifteen hemophilia treatment centers. PATIENTS: A total of 1701 patients with hemophilia, of whom 1065 (63%) were HIV-1 seropositive. MAIN OUTCOME MEASURES: Morphologic classification and incidence rates of cancers. MAIN RESULTS: The incidence of non-Hodgkin's lymphoma after HIV seroconversion averaged 0.15 case per 100 person-years (95% confidence interval [CI], 0.08 to 0.25) and rose exponentially with increasing duration of HIV infection. Although the greatest absolute risk of lymphoma was in the oldest age group, the relative increase compared with general population rates was 38-fold in subjects 10 to 39 years old and 12-fold in older subjects (P less than .05). The CD4+ T-lymphocyte levels for lymphoma cases were similar to HIV-positive subjects without the acquired immunodeficiency syndrome (AIDS) who had been infected for the same length of time. The incidence of Kaposi's sarcoma was increased 200-fold (95% CI, 20 to 700). The incidence of cancers other than non-Hodgkin's lymphoma and Kaposi's sarcoma were not increased in the HIV-positive subjects (ratio of observed to expected cases, 0.9 [95% CI, 0.4 to 1.9]). The HIV-negative subjects had no significant increase in cancer incidence. CONCLUSIONS: HIV infection has restricted effects on cancer incidence that are only partly explained by immunosuppression. Paradoxically, improvements in therapy of HIV infection that prolong survival may lead to further increases in HIV-associated lymphoma.

Acquired Immunodeficiency Syndrome↗