Nonhemolytic antibody-induced loss of erythrocyte surface antigen

Transfusion of red blood cells (RBCs) into patients with anti-donor RBC antibodies (crossmatch-incompatible transfusion) can result in lethal antibody-mediated hemolysis. Less well appreciated is the ability of anti-RBC antibodies to specifically remove their target antigen from donor RBCs without compromising cell survival or adversely affecting the transfusion recipient. In an effort to elucidate the mechanistic details of this process, we describe the first animal model of nonhemolytic antibody-induced RBC antigen loss. RBCs from transgenic mHEL mice express surface hen egg lysozyme (HEL) as a transmembrane protein. Transfusion of mHEL RBCs into mice immunized with HEL results in selective loss of HEL antigen from donor RBCs without affecting other blood group antigens or reducing the circulatory life span of the transfused RBCs. While this process does not require the presence of a spleen, it requires both anti-RBC immunoglobulin G (IgG) antibodies and the FcgammaIII receptor. These studies provide mechanistic insight into the phenomenon of antigen loss during incompatible transfusion in humans.     

Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-beta peptide (Abeta) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Abeta and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Abeta(1-42) levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Abeta burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Abeta burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Abeta burden and the subsequent development of neuritic plaques.     

Assessment of mitral valvar stenosis by echocardiography: utility of various methods before and after mitral valvotomy.

Cross-sectional and Doppler echocardiography are currently the most important non-invasive tests for the evaluation of mitral stenosis. Recent experience has, however, shown that parameters that are reliable before mitral valvotomy may not be valid after the procedure. We have studied the validity of estimation of the area of the mitral valve by echo-planimetry, by Doppler pressure half time and the transmitral end-diastolic pressure gradient calculated by continuous wave Doppler in 100 patients (aged 10-30 years) before and after balloon mitral valvoplasty (n = 70) or surgical closed mitral valvotomy (n = 30). These patients underwent cardiac catheterisation and echocardiographic studies before, immediately after and 8-12 (9.3 +/- 2.2) weeks following balloon valvoplasty or closed valvotomy. The area as estimated echocardiographically correlated well with that obtained by the Gorlin formula before (r = 0.80), but not immediately after (r = 0.67) or on follow up after mitral valvotomy. There was good correlation between Doppler pressure half time and the area as estimated by the Gorlin formula before (r = 0.89) and on follow up after valvotomy (r = 0.82), but the correlation was not as good in the immediate period after valvotomy (r = 0.60). The end-diastolic pressure gradients obtained by Doppler examination and at cardiac catheterisation correlated well with each other before (r = 0.94), immediately after valvotomy (r = 0.92) and on follow up (r = 0.94). Hence, the reliability of estimation of the area of the mitral valve by echo-planimetry and by Doppler pressure half time varies according to the time at which the examination is performed following commissurotomy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological Treatment of Dysphagia in Stroke

The pharynx is important for a normal swallow and it has been suggested that pharmacological agents may play a role in the management of pharyngeal dysphagia, but none have been formally evaluated. A pilot double-blind, placebo-controlled study was undertaken in 17 hospitalized patients with persistent dysphagia 2 weeks after stroke. Patients were randomized to treatment with slow-release nifedipine 30 mg orally (n = 8) or placebo (n = 9) following specialist swallowing assessment and videofluoroscopy to exclude severe dysphagia. Videofluoroscopy was repeated after 4 weeks of treatment. Fourteen patients (active 6, placebo 8) completed the study. Two patients died (active 1, placebo 1) and 1 patient in the active group had to be withdrawn because of progressive heart failure. Initial assessment showed impairment in the pharyngeal phase with delayed triggering of swallow, poor laryngeal elevation, and prolonged pharyngeal transit times in all patients. Silent aspiration was seen in 4 patients (active 2, placebo 2). Improvement in swallowing was seen in 8 patients (active 5, placebo 3) at the end of 4 weeks. There were significant changes in the pharyngeal transit time (mean −1.34 second; 95% C.I. −2.56, −0.11) and swallow delay (mean −1.91 seconds; 95% C.I. −3.58, −0.24) in the active group suggesting improvement in the initiation of pharyngeal contractions and reduction in the time taken for the bolus to transverse the pharynx. A similar change was not seen in the placebo group. It is suggested that pharmacological agents such as nifedipine may have a role in the management of stroke-related dysphagia and merit further investigation.