Rational design of hypoallergens applied to the major cat allergen Fel d 1

BACKGROUND: Allergen-specific immunotherapy is the only treatment for allergic disease providing long-lasting symptom relief. Currently, it is mainly based on the use of crude allergen extracts. The treatment may be improved by the use of genetically engineered allergens, hypoallergens, aiming at a more effective and safer therapy. OBJECTIVE: The aim of this study was to provide a rational design of hypoallergen candidates for immunotherapy by using structural information and knowledge of B and T cell epitopes of an allergen. METHODS: The three-dimensional structure of the major cat allergen Fel d 1 was systematically altered by duplication of selected T cell epitopes and disruption of disulphide bonds. Seven Fel d 1 derivatives were generated and screened for allergenic reactivity in comparison with recombinant Fel d 1 in competition-ELISA. The allergenicity was further evaluated in basophil activation experiments and T cell reactivity was assessed in a lymphoproliferation assay. RESULTS: Three out of seven Fel d 1 derivatives, with two duplicated T cell epitopes and one or two disulphide bonds disrupted, were carefully evaluated. The three derivatives displayed a strong reduction in allergenicity with 400-900 times lower IgE-binding capacity than recombinant Fel d 1. In addition, they induced a lower degree of basophil activation and similar or stronger T cell proliferation than recombinant Fel d 1. CONCLUSION: By a rational approach, we have constructed three Fel d 1 hypoallergens with reduced IgE-binding capacities and retained T cell reactivities. This strategy may be applied to any well-characterized allergen to improve immunotherapy for allergic patients.     

Phosphoinositide hydrolysis linked 5-HT2 receptors in fibroblasts from choroid plexus

A serotonin (5-HT)-mediated phosphoinositide hydrolysis response was characterized in fibroblasts cultured from rabbit choroid plexus. 5-HT elicited a maximum 8-fold increase in [³H]inositol-phosphate ([³H]IP) formation, while the partial agonists, (+)-lysergic acid diethylamide and (−)-1-(4-bromo-2,5-dimethyoxyphenyl)-2-aminopropane caused 2- and 5-fold increases, respectively. Mianserin, ketanserin, and spiperone were equipotent at blocking the 5-HT-mediated response. Thus, agonist and antagonist profiles indicate interactions with 5-HT₂ receptors.     

Short and long latency auditory evoked potentials in traumatic brain injury patients

Short latency auditory nerve and brainstem evoked responses (BAERs) and long latency cortical auditory evoked responses (CAERs) in 75 long-term traumatic brain injury (TBI) cases were compared. CAERs were found to be significantly correlated with clinical disability as measured by the Disability Rating Scale, while BAERs were not. Also, BAER patterns were consistently and significantly less abnormal and less sensitive to overall dysfunction than CAER patterns. Findings support previous observations that BAERs have relatively little utility for evaluating in surviving TBI patients the degree of overall brain impairment. In general, long latency AEP patterns are better able to reflect the extent and severity of brain dysfunction and overall clinical condition than are short latency AEP patterns in long-term severe TBI patients, and these patterns should be obtained routinely in the evaluation of such patients.     

Isolated complete orbital infarction: a common carotid artery occlusion syndrome

When blood flow through the internal and external carotid arteries is completely interrupted by ipsilateral common carotid artery occlusion, the arterial orbital circulation may be more compromised than the brain supply. We studied a pure and extreme example of this situation in a patient who presented with acute orbital infarction, but no cerebral ischemia on clinical, CT and single-photon emission computerized tomography (SPECT) grounds. Ipsilateral blindness corresponded to retinal, choroidal and optic nerve infarction. The pattern of ophthalmoplegia, with relative sparing of adduction, was more compatible with a muscle than a nerve dysfunction, but a reactive dilated pupil, corneal anesthesia, and orbital pain suggested that the intraorbital branches of the ocular motor nerves and ophthalmic division of the trigeminal nerve were not spared. In addition, signs of widespread ocular ischemia were present. Sequential examinations documented the evolution pattern over 1 year. The absence of an orbital collateral supply from the contralateral external carotid and muscular cervical arteries systems, which contrasted with an adequate middle cerebral artery supply via the contralateral internal carotid artery, may explain this isolated and complete form of orbital ischemia due to common carotid artery occlusion.     

Three-dimensional human pattern visual evoked potentials. II. Multiple sclerosis patients.

Pattern visual evoked potentials were obtained from 46 patients with definite relapsing/remitting multiple sclerosis, using both a conventional 5-channel occipital array and a 3-D recording technique consisting of three bipolar derivations approximating the three dimensions of space. These three orthogonal wave forms were displayed as a 3-D Lissajous trajectory for each subject. Two of the 15 patients with completely normal conventional pattern VEPs had abnormalities of the orientation of the B-C curvilinear segment of the 3-D pattern VEPs. Delays in the first major occipital positive component (P100) were evident using both techniques; the correlation between P100 latency and the latency of the corresponding trajectory apex was r = 0.99 (P less than 0.01). Post-chiasmal MRI abnormalities were associated with 3-D VEP orientation abnormalities. Three-dimensional pattern VEPs are moderately more sensitive than conventional pattern VEPs at detecting dysfunction posterior to the optic chiasm in demyelinating disease and do not require the use of eccentric fixation to do so.     

Effect of anesthesia on the impulse activity of hypothalamic neurons in rabbits]

Impulse activity of the anterior and posterior hypothalamus neurons was investigated in the unanaesthetised and anaesthetised (urethan and chloralose) rabbits. Anaesthesia is shown to induce a decrease of the mean firing rate, alteration of the impulse activity pattern and a decrease of the quantity of neurons, responding to the skin thermal stimulation. These changes are expressed most of all in the posterior hypothalamic neurons.     

Changes in women's mental and physical health from pregnancy through six months postpartum

A longitudinal study was conducted to investigate changes in women's mental and physical health around the time of childbirth, and to determine whether health was related to length of maternity leave. Thirty-seven married, employed first-time mothers completed questionnaires during pregnancy, and again at 6 weeks, 3 months, and 6 months postpartum. Results showed that, from pregnancy to the 6th postpartum month, the number of days that mothers were ill because of infections steadily increased. In addition, depressive symptoms for new mothers rose from pregnancy to the 6th week postpartum, and declined thereafter. For women who did not return to work during the period of the study, a significant decline in depressive symptoms was observed from the prenatal period through the 6th postpartum month. These findings demonstrate significant changes in mental and physical health for this group of first-time mothers.