Therapeutic vaccination against chronic viral infections

Chronic viral infections such as those caused by hepatitis B virus, human papilloma virus, herpes simplex virus, and HIV, in theory, present logical targets of active specific immunotherapy. Indeed, immunological mechanisms are involved in several aspects of their pathogenesis and natural course, such as virus persistence, destruction of infected cells and control of viral replication. Therapeutic vaccination could therefore be an adequate replacement for, or adjunct to, existing therapies. Almost all approaches to therapeutic vaccination have been evaluated in those four disease areas. Despite encouraging results in animals none of these attempts has, so far, been completely successful in the human setting. However, with a better understanding of the immunological mechanisms involved in the control of disease successful therapeutic vaccines, used alone or in combination with other therapies, are an achievable goal.     

Bone mineral density and bone metabolism in spondylarthropathies

AIMS: To study the prevalence of osteoporosis in a group of patients with spondyloarthropathy and to investigate bone turnover markers and correlation between bone mineral density and the age at the beginning of the disease. PATIENTS AND METHOD: Patients with spondyloarthropathy as defined by New York and ESSG criteria. Bone mineral density was measured at the lumbar spine and hip with Hologic QDR 1000. Serum levels of osteocalcin, deoxypyridinoline, 25 vitamin D, creatinine and parathyroid hormone were measured. RESULTS: 50 patients were included in the study: 37 men, mean age 40,2+/-13,8 years. Vertebral osteopenia was observed in 34% while femoral osteopenia occurred in 40% of patients. Serum vitamin D was low in 70% of patients without parathyroid hormone or kidney function modification. Markers of bone turn over were increased in 29% of patients. There was no correlation between these biological markers and the bone mineral density. We observed a significative correlation (P=0,02) between the age at the beginning of the disease and the bone mineral density. CONCLUSION: Osteopenia is present in patients with spondyloarthropathy without any correlation with the bone turnover biological markers. We observed a significative correlation between the age at the beginning of the disease and bone mineral density.     

Clinical-scale selective depletion of alloreactive T cells using an anti-CD25 immunotoxin

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for many hematological malignancies. Its efficacy is limited by graft-versus-host disease (GVHD), the leading cause of post-transplant morbidity and mortality. GVHD is mediated by a subpopulation of T cells in the stem cell graft. Ex vivo T cell depletion of all T cells of the graft can prevent development of GVHD but can lead to a delay in immune reconstitution and an increase of potentially lethal opportunistic infections and leukemic relapses. Hypothetically, an approach that enables a selective depletion of the alloreactive donor T cells that cause GVHD while preserving third party (anti-leukemic and anti-microbial) reactivity would be optimal for recipients of HSCT. Our preliminary data demonstrated that an anti-CD25 immunotoxin, which reacts with a cell surface activation antigen, can selectively deplete alloreactive donor T cells activated by non-leukemic recipient white blood cells while preserving the beneficial third-party reactivity in vitro. In this report we describe a method for clinical-scale ex vivo selective depletion of alloreactive donor T cells using the anti-CD25 immunotoxin, RFT5-SMPT-dgRTA. Two logs of alloreactive T cells could be selectively depleted while preserving third party reactivity. This method was reproducible in 10 pre-clinical experiments with 8 HLA-mismatched healthy volunteer pairs and 2 HLA-matched sibling donor/patient pairs.     

Confidence in the diagnosis of early spondylarthropathy: a prospective follow-up of 270 early arthritis patients

OBJECTIVE: To study the confidence of office-based rheumatologists (OBR) and a college of 5 experts in their diagnosis of spondylarthropathy (SpA) for early arthritis after more than 2 years of follow-up; to determine whether at that time the degree of confidence was improved by the fulfilment of the ESSG criteria. METHODS: 270 patients with early-onset (< 1 year) arthritis were prospectively followed-up for 29+/-11 months. At the final examination, OBR and the college of 5 experts rated their confidence in the diagnosis of SpA on a 0-10 analogue scale and on a 1-4 Likert scale, respectively. RESULTS: After 29+/-11 months OBR had classified 56 patients (21%) as SpA, while a collegial diagnosis of probable (N = 32) or certain SpA (N = 14) was made for 46 patients (17%). At the final examination OBR confidence in their diagnosis (gold standard) was only 6.7+/-2.4 for all 56 cases of SpA. The cumulative fulfilment of ESSG criteria for SpA after 29+/-11 months correlated with the confidence of OBR and the experts in SpA, but improved only slightly the final confidence of OBR (7.1+/-2.3 versus 6.7+/-2.4 for all 56 SpA). Similarly, OBR confidence for the 18/56 SpA patients positive for HLA-B27 was only 7.1+/-2.0. Only 21 of these 56 patients were considered as SpA at baseline, although 37/56 (66%) had fulfilled ESSG criteria since thefirst examination. CONCLUSION: This study indicates a probable lack of consensus on the nosology of early SpA and the limited help provided by the ESSG criteria to differentiate early SpA from otherforms of arthritis at baseline.     

Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center

BACKGROUND/AIMS: The natural history of chronic hepatitis C (HCV) is not completely understood. This study was aimed to evaluate the long-term outcome of the disease over a prolonged period of time and to identify factors associated with progression. METHODS: One hundred and sixteen patients with non-cirrhotic chronic non-A, non-B hepatitis consecutively diagnosed at a tertiary hospital between 1971 and 1977 were followed until December 1998 or until death. Patients with significant alcohol intake were excluded from the study. Variables obtained at the time of diagnosis, including epidemiological, clinical, laboratory, and histological data were recorded to determine risk factors associated with the development of liver cirrhosis and hepatic decompensation. RESULTS: Based on complete follow-up data, the development of liver cirrhosis and hepatic decompensation was evaluated in 94 and 114 of the 116 patients, respectively. Thirty-seven (39.3%) of 94 patients developed liver cirrhosis; an aspartate aminotransferase (AST) value higher than 70 IU/L was associated with development of cirrhosis (odds ratio (OR) 4.22, 95% CI 1.3-13.8). Hepatic decompensation occurred in 12 (10.5%) of 114 patients, its cumulative probability being 2.8% at 10 years, 5.2% at 15 years and 19.8% at 20 years. The only factor independently associated to the development of hepatic decompensation was the presence of fibrosis (stage 2 or 3) in the initial liver biopsy (OR 4.1, IC 95% 1.22-13.9). Liver-related death occurred only in seven (6%) of 114 patients. In comparison with the 116 patients diagnosed in the 1970's, patients with chronic hepatitis C diagnosed in 1999 were younger, more often asymptomatic, had lower AST and alanine aminotransferase (ALT) values and had significantly lower grade and stage histological scores. CONCLUSIONS: In summary, chronic hepatitis C had a high rate of progression to liver cirrhosis over a prolonged follow-up. However, this might be related to the fact that two decades ago the diagnosis was made at a significantly more advanced stage of the disease. Patients at high risk of progression can be identified by biochemical and histological variables at the time of diagnosis.     

Risk factors for diffuse and focal macular edema

OBJECTIVE: The epidemiological risk factors for the different forms of diabetic macular edema (focal or diffuse) are not differentiated in the literature. In the present study, the objective was to determine which risk factors influence the appearance of focal or diffuse macular edema. RESEARCH, DESIGN, AND METHODS: A 4-year prospective study in a population of Type II diabetic patients (NIDDM) in three groups, the first with 29 patients with diffuse diabetic macular edema (Group A), the second with 32 patients with focal macular edema (Group B), and the third with 32 patients with diabetic retinopathy but without diabetic macular edema (Group C); the three groups were selected on the basis of sex, age, and duration of diabetes with similar patterns. We studied the following risk factors: treatment of diabetes mellitus by insulin, presence of diastolic blood hypertension, presence of microalbuminuria or diabetic nephropathy, levels of HbA1c, type of diabetic retinopathy, presence of previous panretinal photocoagulation, and levels of triglycerides and fractions of cholesterol. RESULTS: In discriminant analysis and in order of importance, the epidemiological risk factors for Group A were the following: presence of panretinal laser, diastolic blood hypertension, diabetic nephropathy, and insulin treatment; for group B, the risk factors were the following: insulin treatment, presence of diastolic blood hypertension, and high levels of glycated haemoglobin (HbA1c); and for group, C the risk factors were the following: diastolic blood hypertension, insulin treatment of diabetes, and high levels of HbA1c. CONCLUSIONS: In the present study, the group of patients with focal macular edema were epidemiologically similar to the group of patients with diabetic retinopathy without macular edema, the group of patients with diffuse macular edema were epidemiologically different.     

Therapeutic erythrocytapheresis: technical aspects and clinical applications

PURPOSE: Therapeutic erythrocytapheresis is a selective red cell-depletion aphaeresis technique. CURRENT KNOWLEDGE AND KEY POINT: Using a discontinuous or continuous flow blood cell separator, the technique safely allows quickly and automatically collecting a large volume of red cells. The main obstacle of implementation is a poor peripheral venous access. The procedure is well-tolerated. Polycythemia vera, hereditary hemochromatosis, complicated sickle-cell-disease and retinal venous occlusion are the main clinical applications. PROSPECT AND PROJECT: Therapeutic erythrocytapheresis is a more modern and more effective method than the classic patient-bleeding. It has to be preferred in the early treatment of patients with polycythemia vera and hereditary hemochromatosis.     

Silent ischemia and acute cardiac insufficiency with normal systolic function: diagnostic value of troponin I measurement

The physiopathological mechanisms resulting in increased left ventricular pressures in acute cardiac failure with normal systolic function are not well understood. Although coronary artery disease is commonly associated with acute episodes, the diagnostic value of troponin I measurement and the prevalence of ischaemia as the predisposing factor are not known. Twenty coronary patients (mean age 77 +/- 9 years) in acute cardiac failure with left ventricular ejection fractions of 50% or over and without angina, were studied retrospectively. The diagnostic value of troponin I (cTnI, AxSYM, method) was assessed by comparing with a control group of 16 acute cardiac failure patients without coronary disease. The frequency of hypertension and diabetes in the coronary group was 50 and 45% respectively. At the time of investigation, the pulmonary capillary and systemic arterial pressures were comparable in the coronary patients irrespective of the cTnl value. At threshold levels of 0.5 microgram/l, cTnl had a specificity of 100% and confirmed ischaemia in 60% of the coronary patients. Ischaemia was the commonest predisposing factor for increased cardiac pressures. Over a 268 +/- 101 days follow-up period, half the coronary patients were readmitted for acute cardiac failure and a third of them died. The authors conclude that silent ischaemia is a common predisposing factor for acute cardiac failure in coronary patients with normal systolic function and troponin I measurement is a useful diagnostic help.     

Hypoxemia after heart surgery by a right-left shunt via a permeable unrecognized foramen ovale

Hypoxemia is a relatively common complication in the immediate postoperative period after cardiac surgery under cardio-pulmonary bypass, usually due to pulmonary disease. When this does not improve with oxygen therapy and in the absence of pulmonary disease, it may be due to a right-to-left shunt. We report a case with a right-to-left intracardiac shunt due to persistence of a patent foramen ovale, which became functional again under the new hemodynamic conditions after surgery under cardiopulmonary bypass and assisted ventilation. The diagnosis and physiopathological mechanism were studied by cardiac catheterisation and angiography. Contrast echocardiography should be able to detect these acquired shunts relatively easily. The diagnosis requires appropriate therapy: discontinuation of ineffective assisted ventilation as this may aggravate the situation by increasing pulmonary resistance, and anticoagulant therapy to prevent potentially disastrous paradoxical thromboembolism.