A functional assay for proteolytic processing of the amyloid precursor protein (APP) was set up in yeast. This consisted of a membrane-bound chimeric protein containing the beta-secretase cleaved C-terminal fragment of APP fused to the Ga14 transcription factor. Using this chimera in a GAL-reporter yeast strain, an expression library of human cDNAs was screened for clones that could activate the GAL-reporter genes by proteolytic processing of the membrane-bound APP-Gal4. Two human proteases, caspase-3 and caspase-8, were identified and confirmed to act by a mechanism that involved proteolysis at the site in the APP-Gal4 chimera that corresponded to the natural caspase cleavage site in APP, thus linking a readily scorable phenotype to proteolytic processing of APP. The activation of caspase-3 involved a mechanism that was independent of aspartic acid residue 175 at the cleavage site normally required for processing of caspase-3.

A CASE OF ADIPOSIS DOLOROSA. but then there is usually slight pain between the paroxysms.

It will thus be seen that exophthalmic goltre is by no means a harmless malady; but, of the eleven who died, the death can only be attributed to Graves's disease in two-namely, those which died suddenly; for sudden death is always cardiac; and, as the patients had suffered from palpitation, it is only fair to assume that the same cause as set up the palpitation, in some way was the reason of the sudden death.In the mitral regurgitant case, the mitral disease seemed more related to the antecedent rheumatic fever than the exophthalmic goitre.With regard to the treatment, Jane A., who did best of all the cases, had no treatment; Alice M. benefitted considerably from the local' application of iced water; Ellen E. ' and two are liable to neuralgia; in many cases, no doubt, these points were not asked, for it may be taken that the usually stated association with neurotic tendencies is true ; four cases, at least, had menstrual irregularities, and one patient stated that the exophthalmos was greater during the periods. The temperature was slightly raised in some cases (it was so in one in which the report does not mention the fact), and the pulseis accelerated out of proportion to the rise of temperature. The palpitation is usually the first symptom to appear (in two cases, it had existed all the patient's life); the enlarged thyroid and exophthalmos come second in order in about equal proportions, the exophthalmos being last rather more frequently than the other; as arule, all these symptoms come on within a few weeks of each other.The case of Alice M. G. is especially interesting, for I learn that tlie two sisters referred to also have exophthalmic goitre. Although it is not so well brought out as it should be in these abstracts, several of the patients suffer from wasting. In some cases, the eye s painfu4; but whether that is due to the conjunctivitis, or to the tension of the lids caused by the protrusion, is not stated.I have grouped all the above facts together, because they are all known to be frequent accompaniments of exophthalmic goitre; but the second group of conditions to which I would direct attention is that of the lymphatic system. Four of the twelve cases died within the hospital; one of these four died from heart-disease,.and, of.the remaining three, all suffered from some affection, of the lymphatic systel; thus, in Charlotte S., the thymus was persistent, and Peyer's patchqs were particularly well marked; in Mary M., the thymus was elarged and persistent, Peyer's patches and the solitary follicles of the whole intestine were much swollen, injected, and very prominent, and t* intestine itself was considerably injected; in Eliza T., Peyer's patches at the lower part of the ilem were of -a dark livid character, cntrasti_ g most strongly with the surrounding intestine, which was injectd.

The medical man who was called in sent her to a pay-bed in the general ward of a hospital. She had many medicines, but she says they all made her worse. Massage was tried, but it did no good, and the patient evidently had a great dislike to the nurse to whom -the massage was entrusted. During her illness she frequently has had erythematous rashes on the body. As after six or seven months' stay in the hospital she had not improved, she left. I found her reduced to a mere skeleton, vomiting everything she took, oven plain water. There was some pain and tenderness over the stomach, and a faint systolic mnnrmur. I refused to have an thing to do with the case unless I was allowed to isolate her completely for as long as I liked, but said that if this were granted I could almost promise that she would be well in about mx weeks The friends agreed; lodgings were taken for the patient, and a suitable nurse was found. Kis--arrived at her lodgings on the evening of April 9th. She was so week and thin that the opinion of those who carried her up. stairs was that "she would never go away except in a coffin." During the first six days she had milk in small quantities, and at frequent intervals, beginning with half a pint and reaching three pints on the sixth day. Then she was allowed a little jelly, and some of the milk was just coloured with tea.

No abstract